Methods of treating overactive bladder using trospium

ABSTRACT

The present application provides methods of treating overactive bladder and methods of training or retraining bladder, prolonging symptom relief, improving the quality of life and/or neuronal remodeling in an individual having overactive bladder, by administering an effective amount of trospium locally to the bladder of the individual for at least about 24 hours.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of, and priority to U.S. provisionalapplication 62/713,414, filed Aug. 1, 2018 and U.S. provisionalapplication 62/850,481 filed May 20, 2019. The contents of each of theseapplications are incorporated herein by reference in their entireties.

TECHNICAL FIELD

The present application relates to methods of treating overactivebladder, training or retraining bladder, prolonging symptom relief,improving the quality of life and/or neuronal remodeling in anindividual having overactive bladder, by locally delivering trospium tothe bladder.

BACKGROUND

Lower urinary tract disorders, including overactive bladder, detrusorinstability, and urinary incontinence can arise from numerouspathologies. These pathologies are commonly classified as neuropathic,myogenic, or idiopathic. The majority of patients usually arecharacterized as idiopathic due to the lack of observable diseaseetiology.

Recent studies have suggested the sensory system of the urothelium mayplay an important role in afferent signaling and detrusor activity. Seede Groat and Yoshimura, Handb Exp Pharmacol. 2009; (194): 91-138; Dalyet al. Current Opinion in Urology 2011, 21:268-274; Birder and AnderssonPhysiol Rev 93: 653-680, 2013. Pathologies of this system have beensuggested to play a significant role in many patients with lower urinarytract idiopathic disease.

Standard drug therapies for patients with idiopathic lower urinary tractdisorders are systemic treatments typically administered orally ortrans-dermally. These therapies often lack adequate efficacy due toeither dose limiting side effects, low potency, or both.

Currently patients failing systemic drug therapy have only twoalternatives. The first alternative is Botox injections directly intothe bladder wall, which may provide symptom relief, but which alsoundesirably can produce prolonged urinary retention requiringself-catheterization. The second alternative is neurosacral stimulationas produced by the InterStim® device which is surgically implanted andshown to provide symptomatic relief. However, the equipment and surgicalprocedure is expensive, highly invasive, and carries a 30% adverse eventrate requiring corrective surgeries or removals.

Overactive bladder is a chronic condition characterized by the lowerurinary tract symptoms of urinary urgency, with or without urgeincontinence, usually with urinary frequency and nocturia. Overactivebladder is the most common cause of urinary incontinence or loss ofbladder control in adults and affects approximately 33 million, or about17%, of adults in the U.S.A. Although the prevalence among men and womenin the U.S.A. is similar (16.0% vs. 16.9%, respectively), the severityand nature of symptom expression does differ, with women demonstrating ahigher incidence of urge incontinence. There is also a marked increasein prevalence with increasing age. Overactive bladder has a significantimpact on the health-related quality of life, mental health, and qualityof sleep of affected individuals; whether or not they display thesymptom of urge incontinence. The economic burden of overactive bladderis also significant, estimated at approximately $12 billion per annum inthe U.S.A. alone. Overactive bladder is distinct from stress urinaryincontinence, but when they occur together is usually known as mixedincontinence.

The urothelial sensory system is comprised of numerous receptors andsignaling pathways, many of which exhibit significant “cross talk.” Dueto the complexity of the urothelial sensory system, selective agents,such as darifenasin, may not adequately modulate urothelial sensoryactivation following nonspecific noxious stimuli. Similarly,non-specific agents, such as oxybutynin which exhibits antimuscarinicand calcium channel activity, do not inhibit urothelial response asmeasured by intercontraction intervals but can lead to urinaryretention.

Accordingly, there remains a need for more and better treatment optionsfor lower urinary tract disorders, including overactive bladder.Desirably, such treatments would address one or more of the problemsassociated with systemic administration of drugs and with highlyinvasive and expensive surgical procedures. Desirably, the treatmentwould also avoid or lessen the need for painful injections and repeatedself-catheterization. Desirably, the treatment would generate asustainable response.

The disclosures of all publications, patents, patent applications andpublished patent applications referred to herein are hereby incorporatedherein by reference in their entirety.

SUMMARY

In some embodiments, provided herein is a method of training the bladderof an individual having overactive bladder comprising administering aneffective amount of trospium locally to the bladder of the individualfor at least about 24 hours.

In some embodiments, provided herein is a method of prolonging symptomrelief for an individual having overactive bladder comprisingadministering an effective amount of trospium locally to the bladder forat least about 24 hours, wherein the individual experiences relief of asymptom for at least about 24 hours after trospium administration iscompleted.

In some embodiments, provided herein is a method of improving thequality of life of an individual having overactive bladder comprisingadministering an effective amount of trospium locally to the bladder forat least about 24 hours, wherein the quality of life of the individualis improved upon treatment with trospium.

In some embodiments according to any of the methods described above, theindividual having overactive bladder experiences at least about 50% ofbaseline symptom relief for at least about 7 days after trospiumadministration is completed.

In some embodiments according to any of the methods described above,trospium is continuously administered locally to the bladder for atleast about 42 days.

In some embodiments according to any of the methods described above, themethod further comprises administering an effective amount of trospiumlocally to the bladder about every 3 months or on an as needed (prn)basis.

In some embodiments, provided herein is method of treating overactivebladder comprising continuously administering an effective amount oftrospium locally to the bladder of the individual for at least about 42days.

In some embodiments according to any of the methods described above,trospium is continuously administered for about 56 days, or about 12weeks. In some embodiments, trospium is continuously administered for atleast about 12 weeks.

In some embodiments also provided herein is a method of maintenancetherapy for overactive bladder in an individual comprising administeringtrospium continuously and locally to the bladder for at least about 24hours, wherein the individual has received a previous therapy foroveractive bladder. In some embodiments, the maintenance therapycomprises administering an effective amount of trospium locally to thebladder for at least about 24 hours every 3 months. In some embodiments,the maintenance therapy comprises administering an effective amount oftrospium locally to the bladder for at least about 24 hours on an asneeded (prn) basis. In some embodiments, the maintenance therapycomprises administering an effective amount of trospium locally to thebladder for at least about 24 hours upon symptom recurrence. In someembodiments, the maintenance therapy comprises administering aneffective amount of trospium locally to the bladder for at least about24 hours when the individual experiences at least a 50% recurrence inbaseline symptoms. In some embodiments, the previous therapy comprisesadministering an effective amount of trospium locally to the bladder forat least about 24 hours, at least about 42 days, at least about 56 days,or at least about 12 weeks.

In some embodiments according to any of the methods described above, theconcentration of trospium in the bladder is between about 0.1 to 100μg/ml during administration of trospium. In some embodiments, theconcentration of trospium in the plasma of the individual is less thanabout 2 ng/ml during administration of trospium.

In some embodiments according to any of the methods described above, theindividual has idiopathic overactive bladder.

In some embodiments according to any of the methods described above, theindividual has multiple sclerosis, Alzheimer's disease, Parkinson'sdisease, or has previously had a stroke.

In some embodiments according to any of the methods described above, theindividual has failed a previous treatment for overactive bladder.

In some embodiments according to any of the methods described above, theindividual has not received a previous treatment for overactive bladder.

In some embodiments according to any of the methods described above, theindividual has failed or is not eligible for oral therapy.

In some embodiments according to any of the methods described above, theindividual has urinary incontinence or urge incontinence.

In some embodiments according to any of the methods described above, themethod results in neuronal remodeling or remodeling of a neural network.In some embodiments, symptomatic relief of urgency, frequency, orincontinence is achieved. In some embodiments, the quality of life scoreof the individual is improved. In some embodiments, the urinary botherscore of the individual is reduced. In some embodiments, the methodreduces an aberrant urge to urinate.

In some embodiments according to any of the methods described above,trospium is administered to the bladder by using an intravesical device.

BRIEF DESCRIPTION OF THE DRAWINGS

Referring now to the drawings, which are meant to be exemplary and notlimiting, and wherein like elements are numbered alike. The detaileddescription is set forth with reference to the accompanying drawingsillustrating examples of the disclosure, in which use of the samereference numerals indicates similar or identical items. Certainembodiments of the present disclosure may include elements, components,and/or configurations other than those illustrated in the drawings, andsome of the elements, components, and/or configurations illustrated inthe drawings may not be present in certain embodiments.

FIG. 1A is a cross-sectional side view of one embodiment of an elasticportion of a device containing a restraining end plug.

FIG. 1B is a cross-sectional end view of the embodiment of FIG. 1A.

FIG. 1C is a cross-sectional side view of the device of FIG. 1A when thereservoir is not under an osmotic pressure.

FIG. 1D is a cross-sectional side view of the device of FIG. 1A when thereservoir is under an osmotic pressure.

FIG. 2 is a cross-sectional side view of one embodiment of a devicehaving a preformed sidewall orifice and two restraining end plugs.

FIG. 3A is a plan view of one embodiment of a device having a preformedsidewall orifice and two restraining end plugs.

FIG. 3B is a cross-sectional magnified view of one of the end plugs ofFIG. 3A.

FIG. 3C is an exploded perspective view of the end plug of FIG. 3B.

FIG. 4 is a cross-sectional end view of one embodiment of a drugdelivery device.

FIG. 5A is a plan view of one embodiment of a drug delivery devicehaving restraining plugs and a preformed release port.

FIG. 5B is an enlarged cross-sectional view of the device of FIG. 5A.

FIG. 6A is a plan view of one embodiment of a drug delivery devicehaving restraining plugs and a preformed release port.

FIG. 6B is an enlarged cross-sectional view of the device of FIG. 6A.

FIGS. 7A-7C show an intravesical device that can be used to providelocal and continuous delivery of trospium or another therapeutic agent.FIG. 12A is a plan view. FIG. 12B is a cross-sectional view taken alongline 3-3 in FIG. 12A. FIG. 12C is a view of one end portion of thedevice disposed within the working channel of a deployment instrument,which is shown in partial cross-section.

FIG. 8 shows daily urinary recovery of trospium assessed on Day 3, 7,21, 35, 42 and 56 after the insertion of TAR-302.

FIG. 9A and FIG. 9B show the scheme of the study (FIG. 9A) and averagedaily incontinence episodes assessed at Day 0 (baseline), Day 42 and Day84 after the insertion of TAR-302 (FIG. 9B).

FIG. 10A and FIG. 10B show the efficacy of overactive bladdertreatments. FIG. 10A shows the change in daily urge incontinenceepisodes in oral-refractory overactive bladder patients at the end ofdosing after treatment of TAR-302 or Botox®. FIG. 10B shows thereduction in daily urge incontinence episodes in oral naïve overactivebladder patients after treatment of VESIcare® (solifenacin succinate) orDetrol® LA (tolterodine tartrate) as compared to the reduction in dailyurge incontinence episodes in oral-refractory patients after treatmentof TAR-302.

FIG. 11 shows the urinary bother score of individuals treated withTAR-302 calculated prior to treatment with TAR-302, at the end of dosingwith TAR-302 at day 42, and 42 days after TAR-302 was removed at day 84.

FIG. 12 shows the quality of life score of individuals treated withTAR-302 calculated prior to treatment with TAR-302, at the end of dosingwith TAR-302 at day 42, and 42 days after TAR-302 was removed at day 84.

FIG. 13 shows exemplary questionnaire for evaluating bother score.

FIG. 14 shows exemplary questionnaire for evaluating quality of lifescore.

FIGS. 15A and 15B show the scheme of the study (FIG. 15A) and averagedaily incontinence episodes assessed at Day 0 (baseline), Day 14, Day 56and Day 84 after the insertion of TAR-302 (FIG. 15B).

DETAILED DESCRIPTION

The present application is at least partly based upon Applicant'sstriking finding that administering an effective amount of trospiumlocally (e.g., intravesically) into the bladder of an individual havingoveractive bladder can result in prolonged symptom relief (e.g., reducedurinary incontinence). In a phase I clinical trial TAR-302, a passive,nonresorbable trospium-releasing intravesical system whose primary modeof action is the controlled release of trospium into the bladder over aperiod of about 42 days, was shown not only to reduce incontinenceepisodes during the 42 days during which trospium was administered tothe bladder but also surprisingly and significantly reduced incontinenceepisodes in the six weeks after trospium administration was terminated.The present methods has substantial benefits over previous methods ofbladder treatment including oral therapy with trospium, such as reducedside effects along with a higher concentration of trospium locally inthe bladder. Thus in some aspects, the present invention is especiallysuitable for individuals who have idiopathic overactive bladder, havefailed oral therapy, and/or have severe recalcitrant disease. In someaspects, the present application provides methods of training orretraining the bladder of an individual having overactive bladder. Insome aspects, the present application provides methods of prolongingsymptom relief for an individual having overactive bladder. In someaspects, the present application provides methods of neuronal remodelingin an individual having overactive bladder. In some aspects, the presentapplication provides methods of improving the quality of life in anindividual having overactive bladder.

Definitions

As used herein, the singular forms “a,” “an,” and “the” include pluralreferents unless the context clearly dictates otherwise. For example,“a” or “an” means “at least one” or “one or more.”

The term “individual” as used herein refers to a mammal, includinghumans. An individual includes, but is not limited to, human, bovine,horse, feline, canine, rodent, or primate. In some embodiments, theindividual is human.

The term “effective amount” used herein refers to an amount of acompound or composition sufficient to treat a specified disorder,condition or disease such as to ameliorate, palliate, lessen, and/ordelay one or more of its symptoms.

Reference to “about” a value or parameter herein includes (anddescribes) embodiments that are directed to that value or parameter perse. For example, “about 7 days” includes 7 days.

The term “about X-Y” used herein has the same meaning as “about X toabout Y.” Similarly, “about X to Y” used herein has the same meaning as“about X to about Y.”

As used herein, “treatment” or “treating” is an approach for obtainingbeneficial or desired results including clinical results. For purposesof this invention, beneficial or desired clinical results include, butare not limited to, one or more of the following: alleviating one ormore symptoms resulting from the disease, diminishing the extent of thedisease, stabilizing the disease (e.g., preventing or delaying theworsening of the disease), preventing or delaying the recurrence of thedisease, delaying or slowing the progression of the disease,ameliorating the disease state, decreasing the dose of one or more othermedications required to treat the disease, delaying the progression ofthe disease, and/or increasing or improving the quality of life. Themethods of the invention contemplate any one or more of these aspects oftreatment.

Methods

The present application in one aspect provides a method of training (orretraining) the bladder of an individual having overactive bladdercomprising administering an effective amount of trospium locally to thebladder of the individual for at least about 24 hours. In someembodiments, trospium is administered for at least about 3, 5, or 7days. In some embodiments, trospium is administered for at least about2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks. In someembodiments, trospium is administered by using an intravesical deliverydevice. In some embodiments, trospium is administered at a dose of aboutfrom 1 mg/day to 100 mg/day, from about 1 mg/day to 20 mg/day, fromabout 2 mg/day to 10 mg/day, from about 4 mg/day to 8 mg/day. In someembodiments, the concentration of trospium in the urine is about 0.1μg/mL to about 20 μg/mL, about 1 μg/mL to about 10 μg/mL, about 2 μg/mLto about 8 μg/mL, about 3 μg/mL to about 7 μg/mL, or about 3 μg/mL toabout 5 μg/mL during trospium administration. In some embodiments,trospium is administered continuously or intermittently. In someembodiments, the individual having overactive bladder experiences atleast about 50% of baseline symptom relief for at least about 7 days, 2weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks after trospiumadministration is completed. In some embodiments, the individual has aprior therapy for overactive bladder. In some embodiments, the priortherapy is an oral therapy. In some embodiments, the individual does notrespond or is refractory to the prior therapy. In some embodiments, theindividual is human. In some embodiments, the individual has idiopathicoveractive bladder. In some embodiments, the individual has multiplesclerosis, Alzheimer's disease, Parkinson's disease, or has previouslyhad a stroke.

The present application also provides a method of training (orretraining) the bladder of an individual having overactive bladdercomprising administering an effective amount of trospium locally to thebladder of the individual for at least about 42 days (e.g., about 42,56, 70, or 84 days). In some embodiments, trospium is administered forat least about 56 days. In some embodiments, trospium is administeredfor at least about 100 days. In some embodiments, trospium isadministered by using an intravesical delivery device. In someembodiments, trospium is administered at a dose of about from 1 mg/dayto 100 mg/day, from about 1 mg/day to 20 mg/day, from about 2 mg/day to10 mg/day, from about 4 mg/day to about 8 mg/day. In some embodiments,the concentration of trospium in the urine is about 0.1 μg/mL to about20 μg/mL, about 1 μg/mL to about 10 μg/mL, about 2 μg/mL to about 8μg/mL, about 3 μg/mL to about 7 μg/mL, or about 3 μg/mL to about 5 μg/mLwhile trospium is administered. In some embodiments, trospium isadministered continuously or intermittently. In some embodiments, theindividual having overactive bladder experiences at least about 50% ofbaseline symptom relief for at least about 7 days, 2 weeks, 3 weeks, 4weeks, 5 weeks, or 6 weeks after trospium administration is completed.In some embodiments, the individual has a prior therapy for overactivebladder. In some embodiments, the prior therapy is an oral therapy. Insome embodiments, the individual does not respond or is refractory tothe prior therapy. In some embodiments, the individual is human. In someembodiments, the individual has idiopathic overactive bladder. In someembodiments, the individual has multiple sclerosis, Alzheimer's disease,Parkinson's disease, or has previously had a stroke.

The present application also provides a method of training (orretraining) the bladder of an individual having overactive bladdercomprising administering an effective amount of trospium locally to thebladder of the individual for at least about 42 days (e.g., about 42,56, 70, or 84 days), wherein the individual has had a prior therapy, andwherein the individual is refractory to the prior therapy. In someembodiments, trospium is administered for at least about 56 days. Insome embodiments, trospium is administered for at least about 84 days.In some embodiments, trospium is administered for at least about 100days. In some embodiments, the prior therapy is an oral therapy. In someembodiments, trospium is administered by using an intravesical deliverydevice. In some embodiments, trospium is administered at a dose of aboutfrom 1 mg/day to 100 mg/day, from about 1 mg/day to 20 mg/day, fromabout 2 mg/day to 10 mg/day, from about 4 mg/day to about 8 mg/day. Insome embodiments, the concentration of trospium in the urine is about0.1 μg/mL to about 20 μg/mL, about 1 μg/mL to about 10 μg/mL, about 2μg/mL to about 8 μg/mL, about 3 μg/mL to about 7 μg/mL, or about 3 μg/mLto about 5 μg/mL while trospium is administered. In some embodiments,trospium is administered continuously or intermittently. In someembodiments, the individual having overactive bladder experiences atleast about 50% of baseline symptom relief for at least about 7 days, 2weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks after trospiumadministration is completed. In some embodiments, the individual ishuman. In some embodiments, the individual has idiopathic overactivebladder. In some embodiments, the individual has multiple sclerosis,Alzheimer's disease, Parkinson's disease, or has previously had astroke.

The present application in another aspect provides a method ofprolonging symptom relief for an individual having overactive bladdercomprising administering an effective amount of trospium locally to thebladder for at least about 24 hours, wherein the individual experiencesrelief of a symptom for at least about 24 hours after trospiumadministration is completed. In some embodiments, a prolonged symptomrelief of urgency, frequency, urinary incontinence and/or urgeincontinence is achieved. In some embodiments, the individualexperiences relief of a symptom for at least about 1, 2, 3, 4, 5, or 6weeks after trospium administration is completed. In some embodiments,trospium is administered for at least about 3, 5, or 7 days. In someembodiments, trospium is administered for at least about 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks. In some embodiments,trospium is administered by using an intravesical delivery device. Insome embodiments, trospium is administered at a dose of about from 1mg/day to 100 mg/day, from about 1 mg/day to 20 mg/day, from about 2mg/day to 10 mg/day, from about 4 mg/day to about 8 mg/day. In someembodiments, the concentration of trospium in the urine is about 0.1μg/mL to about 20 μg/mL, about 1 μg/mL to about 10 μg/mL, about 2 μg/mLto about 8 μg/mL, about 3 μg/mL to about 7 μg/mL, or about 3 μg/mL toabout 5 μg/mL while trospium is administered. In some embodiments,trospium is administered continuously or intermittently. In someembodiments, the individual having overactive bladder experiences atleast about 50% of baseline symptom relief for at least about 7 days, 2weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks after trospiumadministration is completed. In some embodiments, the individual has aprior therapy for overactive bladder. In some embodiments, the priortherapy is an oral therapy. In some embodiments, the individual does notrespond or is refractory to the prior therapy. In some embodiments, theindividual is human. In some embodiments, the individual has idiopathicoveractive bladder. In some embodiments, the individual has multiplesclerosis, Alzheimer's disease, Parkinson's disease, or has previouslyhad a stroke.

The present application also provides a method of prolonging symptomrelief for an individual having overactive bladder comprisingadministering an effective amount of trospium locally to the bladder forat least about 42 days (e.g., about 42, 56, 70, or 84 days), wherein theindividual experiences relief of a symptom for at least about 24 hoursafter trospium administration is completed. In some embodiments, aprolonged symptom relief of urgency, frequency, urinary incontinenceand/or urge incontinence is achieved. In some embodiments, theindividual experiences relief of a symptom for at least about 1, 2, 3,4, 5, or 6 weeks after trospium administration is completed. In someembodiments, trospium is administered for at least about 56 days. Insome embodiments, trospium is administered for at least about 84 days.In some embodiments, trospium is administered for at least about 100days. In some embodiments, trospium is administered by using anintravesical delivery device. In some embodiments, trospium isadministered at a dose of about from 1 mg/day to 100 mg/day, from about1 mg/day to 20 mg/day, from about 2 mg/day to 10 mg/day, from about 4mg/day to about 8 mg/day. In some embodiments, the concentration oftrospium in the urine is about 0.1 μg/mL to about 20 μg/mL, about 1μg/mL to about 10 μg/mL, about 2 μg/mL to about 8 μg/mL, about 3 μg/mLto about 7 μg/mL, or about 3 μg/mL to about 5 μg/mL while trospium isadministered. In some embodiments, trospium is administered continuouslyor intermittently. In some embodiments, the individual having overactivebladder experiences at least about 50% of baseline symptom relief for atleast about 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks aftertrospium administration is completed. In some embodiments, theindividual has a prior therapy for overactive bladder. In someembodiments, the prior therapy is an oral therapy. In some embodiments,the individual does not respond or is refractory to the prior therapy.In some embodiments, the individual is human. In some embodiments, theindividual has idiopathic overactive bladder. In some embodiments, theindividual has multiple sclerosis, Alzheimer's disease, Parkinson'sdisease, or has previously had a stroke.

The present application also provides a method of prolonging symptomrelief for an individual having overactive bladder comprisingadministering an effective amount of trospium locally to the bladder forat least about 42 days (e.g., about 42, 56, 70, or 84 days), wherein theindividual experiences relief of a symptom for at least about 24 hoursafter trospium administration is completed (such as at least about 2, 5,7, 10, 15, 20, 25, 30, 35, 40 days after the completion of trospiumadministration), wherein the individual has a prior therapy, and whereinthe individual is refractory to the prior therapy. In some embodiments,a prolonged symptom relief of urgency, frequency, urinary incontinenceand/or urge incontinence is achieved. In some embodiments, theindividual experiences relief of a symptom for at least about 1, 2, 3,4, 5, or 6 weeks after trospium administration is completed. In someembodiments, trospium is administered for at least about 56 days. Insome embodiments, trospium is administered for at least about 84 days.In some embodiments, trospium is administered for at least about 100days. In some embodiments, the prior therapy is an oral therapy. In someembodiments, trospium is administered by using an intravesical deliverydevice. In some embodiments, trospium is administered at a dose of aboutfrom 1 mg/day to 100 mg/day, from about 1 mg/day to 20 mg/day, fromabout 2 mg/day to 10 mg/day, from about 4 mg/day to about 8 mg/day. Insome embodiments, the concentration of trospium in the urine is about0.1 μg/mL to about 20 μg/mL, about 1 μg/mL to about 10 μg/mL, about 2μg/mL to about 8 μg/mL, about 3 μg/mL to about 7 μg/mL, or about 3 μg/mLto about 5 μg/mL while trospium is administered. In some embodiments,trospium is administered continuously or intermittently. In someembodiments, the individual having overactive bladder experiences atleast about 50% of baseline symptom relief for at least about 7 days, 2weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks after trospiumadministration is completed. In some embodiments, the individual ishuman. In some embodiments, the individual has idiopathic overactivebladder. In some embodiments, the individual has multiple sclerosis,Alzheimer's disease, Parkinson's disease, or has previously had astroke.

The present application in another aspect provides a method of neuronalremodeling in an individual having overactive bladder comprisingadministering an effective amount of trospium locally to the bladder forat least about 24 hours, wherein the neuronal remodeling persists for atleast about 24 hours after trospium administration is completed (such asat least about 2, 5, 7, 10, 15, 20, 25, 30, 35, 40 days after thecompletion of trospium administration). In some embodiments, trospium isadministered for at least about 3, 5, or 7 days. In some embodiments,trospium is administered for at least about 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, or 16 weeks. In some embodiments, trospium isadministered by using an intravesical delivery device. In someembodiments, trospium is administered at a dose of about from 1 mg/dayto 100 mg/day, from about 1 mg/day to 20 mg/day, from about 2 mg/day to10 mg/day, from about 4 mg/day to about 8 mg/day. In some embodiments,the concentration of trospium in the urine is about 0.1 μg/mL to about20 μg/mL, about 1 μg/mL to about 10 μg/mL, about 2 μg/mL to about 8μg/mL, about 3 μg/mL to about 7 μg/mL, or about 3 μg/mL to about 5 μg/mLwhile trospium is administered. In some embodiments, trospium isadministered continuously or intermittently. In some embodiments, theindividual having overactive bladder experiences at least about 50% ofbaseline symptom relief for at least about 7 days, 2 weeks, 3 weeks, 4weeks, 5 weeks, or 6 weeks after trospium administration is completed.In some embodiments, the individual has a prior therapy for overactivebladder. In some embodiments, the prior therapy is an oral therapy. Insome embodiments, the individual does not respond or is refractory tothe prior therapy. In some embodiments, the individual is human. In someembodiments, the individual has idiopathic overactive bladder. In someembodiments, the individual has multiple sclerosis, Alzheimer's disease,Parkinson's disease, or has previously had a stroke.

The present application in another aspect provides a method of neuronalremodeling in an individual having overactive bladder comprisingadministering an effective amount of trospium locally to the bladder forat least about 42 days (e.g., about 42, 56, 70, or 84 days), wherein theneuronal remodeling persists for at least about 24 hours after trospiumadministration is completed (such as at least about 2, 5, 7, 10, 15, 20,25, 30, 35, 40 days after the completion of trospium administration). Insome embodiments, trospium is administered for at least about 56 days.In some embodiments, trospium is administered for at least about 84days. In some embodiments, trospium is administered for at least about100 days. In some embodiments, trospium is administered by using anintravesical delivery device. In some embodiments, trospium isadministered at a dose of about from 1 mg/day to 100 mg/day, from about1 mg/day to 20 mg/day, from about 2 mg/day to 10 mg/day, from about 4mg/day to about 8 mg/day. In some embodiments, the concentration oftrospium in the urine is about 0.1 μg/mL to about 20 μg/mL, about 1μg/mL to about 10 μg/mL, about 2 μg/mL to about 8 μg/mL, about 3 μg/mLto about 7 μg/mL, or about 3 μg/mL to about 5 μg/mL while trospium isadministered. In some embodiments, trospium is administered continuouslyor intermittently. In some embodiments, the individual having overactivebladder experiences at least about 50% of baseline symptom relief for atleast about 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks aftertrospium administration is completed. In some embodiments, theindividual has a prior therapy for overactive bladder. In someembodiments, the prior therapy is an oral therapy. In some embodiments,the individual does not respond or is refractory to the prior therapy.In some embodiments, the individual is human. In some embodiments, theindividual has idiopathic overactive bladder. In some embodiments, theindividual has multiple sclerosis, Alzheimer's disease, Parkinson'sdisease, or has previously had a stroke.

The present application in another aspect provides a method of neuronalremodeling in an individual having overactive bladder comprisingadministering an effective amount of trospium locally to the bladder forat least about 42 days (e.g., about 42, 56, 70, or 84 days), wherein theneuronal remodeling persists for at least about 24 hours after trospiumadministration is completed (such as at least about 2, 5, 7, 10, 15, 20,25, 30, 35, 40 days after the completion of trospium administration),wherein the individual has a prior therapy, and wherein the individualis refractory to the prior therapy. In some embodiments, trospium isadministered for at least about 56 days. In some embodiment, trospium isadministered for at least about 56 days. In some embodiments, trospiumis administered for at least about 100 days. In some embodiments, theprior therapy is an oral therapy. In some embodiments, trospium isadministered by using an intravesical delivery device. In someembodiments, trospium is administered at a dose of about from 1 mg/dayto 100 mg/day, from about 1 mg/day to 20 mg/day, from about 2 mg/day to10 mg/day, from about 4 mg/day to about 8 mg/day. In some embodiments,the concentration of trospium in the urine is about 0.1 μg/mL to about20 μg/mL, about 1 μg/mL to about 10 μg/mL, about 2 μg/mL to about 8μg/mL, about 3 μg/mL to about 7 μg/mL, or about 3 μg/mL to about 5 μg/mLwhile trospium is administered. In some embodiments, trospium isadministered continuously or intermittently. In some embodiments, theindividual having overactive bladder experiences at least about 50% ofbaseline symptom relief for at least about 7 days, 2 weeks, 3 weeks, 4weeks, 5 weeks, or 6 weeks after trospium administration is completed.In some embodiments, the individual is human. In some embodiments, theindividual has idiopathic overactive bladder. In some embodiments, theindividual has multiple sclerosis, Alzheimer's disease, Parkinson'sdisease, or has previously had a stroke.

The present application in another aspect provides a method of improvingthe quality of life in an individual having overactive bladdercomprising administering an effective amount of trospium locally to thebladder for at least about 24 hours, wherein the quality of life of theindividual is improved at least about 24 hours after trospiumadministration is completed. In some embodiments, the individual has animproved quality of life score. In some embodiments, the individual hasa reduced urinary bother score. In some embodiments, trospium isadministered for at least about 56 days. In some embodiments, trospiumis administered for at least about 84 days. In some embodiments,trospium is administered for at least about 100 days. In someembodiments, trospium is administered by using an intravesical deliverydevice. In some embodiments, trospium is administered at a dose of aboutfrom 1 mg/day to 100 mg/day, from about 1 mg/day to 20 mg/day, fromabout 2 mg/day to 10 mg/day, from about 4 mg/day to about 8 mg/day. Insome embodiments, the concentration of trospium in the urine is about0.1 μg/mL to about 20 μg/mL, about 1 μg/mL to about 10 μg/mL, about 2μg/mL to about 8 μg/mL, about 3 μg/mL to about 7 μg/mL, or about 3 μg/mLto about 5 μg/mL while trospium is administered. In some embodiments,trospium is administered continuously or intermittently. In someembodiments, the individual having overactive bladder experiences atleast about 50% of baseline symptom relief for at least about 7 days, 2weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks after trospiumadministration is completed. In some embodiments, the individual has aprior therapy for overactive bladder. In some embodiments, the priortherapy is an oral therapy. In some embodiments, the individual does notrespond or is refractory to the prior therapy. In some embodiments, theindividual is human. In some embodiments, the individual has idiopathicoveractive bladder. In some embodiments, the individual has multiplesclerosis, Alzheimer's disease, Parkinson's disease, or has previouslyhad a stroke. In some embodiments, the individual has had anintravesicular device.

The present application in another aspect provides a method of improvingthe quality of life in an individual having overactive bladdercomprising administering an effective amount of trospium locally to thebladder for at least about 42 days (e.g., about 42, 56, 70, or 84 days),wherein the quality of life is improved for at least about 24 hoursafter trospium administration is completed (such as at least about 2, 5,7, 10, 15, 20, 25, 30, 35, 40 days after the completion of trospiumadministration). In some embodiments, the individual has an improvedquality of life score. In some embodiments, the individual has a reducedurinary bother score. In some embodiments, trospium is administered forat least about 56 days. In some embodiments, trospium is administeredfor at least about 84 days. In some embodiments, trospium isadministered for at least about 100 days. In some embodiments, trospiumis administered by using an intravesical delivery device. In someembodiments, trospium is administered at a dose of about from 1 mg/dayto 100 mg/day, from about 1 mg/day to 20 mg/day, from about 2 mg/day to10 mg/day, from about 4 mg/day to about 8 mg/day. In some embodiments,the concentration of trospium in the urine is about 0.1 μg/mL to about20 μg/mL, about 1 μg/mL to about 10 μg/mL, about 2 μg/mL to about 8μg/mL, about 3 μg/mL to about 7 μg/mL, or about 3 μg/mL to about 5 μg/mLwhile trospium is administered. In some embodiments, trospium isadministered continuously or intermittently. In some embodiments, theindividual having overactive bladder experiences at least about 50% ofbaseline symptom relief for at least about 7 days, 2 weeks, 3 weeks, 4weeks, 5 weeks, or 6 weeks after trospium administration is completed.In some embodiments, the individual has a prior therapy for overactivebladder. In some embodiments, the prior therapy is an oral therapy. Insome embodiments, the individual does not respond or is refractory tothe prior therapy. In some embodiments, the individual is human. In someembodiments, the individual has idiopathic overactive bladder. In someembodiments, the individual has multiple sclerosis, Alzheimer's disease,Parkinson's disease, or has previously had a stroke. In someembodiments, the individual has had an intravesicular device.

The present application in another aspect provides a method of improvingthe quality of life in an individual having overactive bladdercomprising administering an effective amount of trospium locally to thebladder for at least about 42 days (e.g., about 42, 56, 70, or 84 days),wherein the quality of life is improved at least about 24 hours aftertrospium administration is completed, wherein the individual has a priortherapy, and wherein the individual is refractory to the prior therapy.In some embodiments, the individual has an improved quality of lifescore. In some embodiments, the individual has a reduced urinary botherscore. In some embodiments, trospium is administered for at least about56 days. In some embodiments, trospium is administered for at leastabout 84 days. In some embodiments, trospium is administered for atleast about 100 days. In some embodiments, trospium is administered byusing an intravesical delivery device. In some embodiments, trospium isadministered at a dose of about from 1 mg/day to 100 mg/day, from about1 mg/day to 20 mg/day, from about 2 mg/day to 10 mg/day, from about 4mg/day to about 8 mg/day. In some embodiments, the concentration oftrospium in the urine is about 0.1 μg/mL to about 20 μg/mL, about 1μg/mL to about 10 μg/mL, about 2 μg/mL to about 8 μg/mL, about 3 μg/mLto about 7 μg/mL, or about 3 μg/mL to about 5 μg/mL while trospium isadministered. In some embodiments, trospium is administered continuouslyor intermittently. In some embodiments, the individual having overactivebladder experiences at least about 50% of baseline symptom relief for atleast about 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks aftertrospium administration is completed. In some embodiments, theindividual has a prior therapy for overactive bladder. In someembodiments, the prior therapy is an oral therapy. In some embodiments,the individual does not respond or is refractory to the prior therapy.In some embodiments, the individual is human. In some embodiments, theindividual has idiopathic overactive bladder. In some embodiments, theindividual has multiple sclerosis, Alzheimer's disease, Parkinson'sdisease, or has previously had a stroke. In some embodiments, theindividual has had an intravesicular device.

Also provided herein is a method of increasing the quality of life scorein an individual comprising administering an effective amount oftrospium locally to the bladder for at least about 42 days (e.g., about42, 56, 70, or 84 days), wherein the quality of life is improved atleast about 24 hours after trospium administration is completed. In someembodiments, improvement of quality of life is measured as an improvedquality of life score. In some embodiments, improvement of quality oflife is measured as a reduced urinary bother score. In some embodiments,trospium is administered for at least about 56 days. In someembodiments, trospium is administered for at least about 84 days. Insome embodiments, trospium is administered for at least about 100 days.In some embodiments, trospium is administered by using an intravesicaldelivery device. In some embodiments, trospium is administered at a doseof about from 1 mg/day to 100 mg/day, from about 1 mg/day to 20 mg/day,from about 2 mg/day to 10 mg/day, from about 4 mg/day to about 8 mg/day.In some embodiments, the concentration of trospium in the urine is about0.1 μg/mL to about 20 μg/mL, about 1 μg/mL to about 10 μg/mL, about 2μg/mL to about 8 μg/mL, about 3 μg/mL to about 7 μg/mL, or about 3 μg/mLto about 5 μg/mL while trospium is administered. In some embodiments,trospium is administered continuously or intermittently. In someembodiments, the individual having overactive bladder experiences atleast about 50% of baseline symptom relief for at least about 7 days, 2weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks after trospiumadministration is completed. In some embodiments, the individual has aprior therapy for overactive bladder. In some embodiments, the priortherapy is an oral therapy. In some embodiments, the individual does notrespond or is refractory to the prior therapy. In some embodiments, theindividual is human. In some embodiments, the individual has idiopathicoveractive bladder. In some embodiments, the individual has multiplesclerosis, Alzheimer's disease, Parkinson's disease, or has previouslyhad a stroke. In some embodiments, the individual has had anintravesicular device.

Provided herein is a method of reducing the urinary bother score in anindividual, comprising administering an effective amount of trospiumlocally to the bladder for at least about 42 days (e.g., about 42, 56,70, or 84 days), wherein the quality of life is improved at least about24 hours after trospium administration is completed. In someembodiments, improvement of quality of life is measured as an improvedquality of life score. In some embodiments, improvement of quality oflife is measured as a reduced urinary bother score. In some embodiments,trospium is administered for at least about 56 days. In someembodiments, trospium is administered for at least about 84 days. Insome embodiments, trospium is administered for at least about 100 days.In some embodiments, trospium is administered by using an intravesicaldelivery device. In some embodiments, trospium is administered at a doseof about from 1 mg/day to 100 mg/day, from about 1 mg/day to 20 mg/day,from about 2 mg/day to 10 mg/day, from about 4 mg/day to about 8 mg/day.In some embodiments, the concentration of trospium in the urine is about0.1 μg/mL to about 20 μg/mL, about 1 μg/mL to about 10 μg/mL, about 2μg/mL to about 8 μg/mL, about 3 μg/mL to about 7 μg/mL, or about 3 μg/mLto about 5 μg/mL while trospium is administered. In some embodiments,trospium is administered for at least about 84 days. In someembodiments, trospium is administered continuously or intermittently. Insome embodiments, the individual having overactive bladder experiencesat least about 50% of baseline symptom relief for at least about 7 days,2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks after trospiumadministration is completed. In some embodiments, the individual has aprior therapy for overactive bladder. In some embodiments, the priortherapy is an oral therapy. In some embodiments, the individual does notrespond or is refractory to the prior therapy. In some embodiments, theindividual is human. In some embodiments, the individual has idiopathicoveractive bladder. In some embodiments, the individual has multiplesclerosis, Alzheimer's disease, Parkinson's disease, or has previouslyhad a stroke. In some embodiments, the individual has had anintravesicular device.

The present application in another aspect provides a method of treatingoveractive bladder comprising continuously administering an effectiveamount of trospium locally to the bladder of the individual for at leastabout 42 days (e.g., about 42, 56, 70, or 84 days). In some embodiments,trospium is administered for at least about 56 days. In someembodiments, trospium is administered for at least about 84 days. Insome embodiments, trospium is administered for at least about 100 days.In some embodiments, trospium is administered by using an intravesicaldelivery device. In some embodiments, trospium is administered at a doseof about from 1 mg/day to 100 mg/day, from about 1 mg/day to 20 mg/day,from about 2 mg/day to 10 mg/day, from about 4 mg/day to about 8 mg/day.In some embodiments, the concentration of trospium in the urine is about0.1 μg/mL to about 20 μg/mL, about 1 μg/mL to about 10 μg/mL, about 2μg/mL to about 8 μg/mL, about 3 μg/mL to about 7 μg/mL, or about 3 μg/mLto about 5 μg/mL while trospium is administered. In some embodiments,trospium is administered continuously or intermittently. In someembodiments, the individual having overactive bladder experiences atleast about 50% of baseline symptom relief for at least about 7 days, 2weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks after trospiumadministration is completed. In some embodiments, the individual has aprior therapy for overactive bladder. In some embodiments, the priortherapy is an oral therapy. In some embodiments, the individual does notrespond or is refractory to the prior therapy. In some embodiments, theindividual is human. In some embodiments, the individual has idiopathicoveractive bladder. In some embodiments, the individual has multiplesclerosis, Alzheimer's disease, Parkinson's disease, or has previouslyhad a stroke.

The present application in another aspect provides a method of treatingoveractive bladder comprising continuously administering an effectiveamount of trospium locally to the bladder of the individual for at leastabout 42 days (e.g., about 42, 56, 70, or 84 days), wherein theindividual has a prior therapy, and wherein the individual is refractoryto the prior therapy. In some embodiments, trospium is administered forat least about 56 days. In some embodiments, trospium is administeredfor at least about 84 days. In some embodiments, trospium isadministered for at least about 100 days. In some embodiments, the priortherapy is an oral therapy. In some embodiments, trospium isadministered by using an intravesical delivery device. In someembodiments, trospium is administered at a dose of about from 1 mg/dayto 100 mg/day, from about 1 mg/day to 20 mg/day, from about 2 mg/day to10 mg/day, from about 4 mg/day to about 8 mg/day. In some embodiments,the concentration of trospium in the urine is about 0.1 μg/mL to about20 μg/mL, about 1 μg/mL to about 10 μg/mL, about 2 μg/mL to about 8μg/mL, about 3 μg/mL to about 7 μg/mL, or about 3 μg/mL to about 5 μg/mLwhile trospium is administered. In some embodiments, trospium isadministered continuously or intermittently. In some embodiments, theindividual having overactive bladder experiences at least about 50% ofbaseline symptom relief for at least about 7 days, 2 weeks, 3 weeks, 4weeks, 5 weeks, or 6 weeks after trospium administration is completed.In some embodiments, the individual is human. In some embodiments, theindividual has idiopathic overactive bladder. In some embodiments, theindividual has multiple sclerosis, Alzheimer's disease, Parkinson'sdisease, or has previously had a stroke.

The present application in another aspect provides a method ofmaintenance therapy for overactive bladder in an individual comprisingadministering trospium continuously and locally to the bladder for atleast about 24 hours, wherein the individual has received a previoustherapy for overactive bladder. In some embodiments, the maintenancetherapy comprises administering an effective amount of trospium locallyto the bladder for at least about 24 hours every 3 months. In someembodiments, the maintenance period comprises administering an effectiveamount of trospium locally to the bladder for at least about 24 hours onan as needed (prn) basis. In some embodiments, the maintenance therapycomprises administering an effective amount of trospium locally to thebladder for at least about 24 hours upon symptom reoccurrence. In someembodiments, the maintenance therapy comprises administering aneffective amount of trospium locally to the bladder for at least about24 hours when the individual experiences at least a 50% recurrence inbaseline symptoms. In some embodiments, the previous therapy comprisesadministering an effective amount of trospium locally to the bladder forat least about 24 hours, at least about 42 days, at least about 56 days,or at least about 84 days. In some embodiments, the prior therapy is anoral therapy. In some embodiments, the individual is refractory to theprior therapy. In some embodiments, trospium is administered by using anintravesical delivery device. In some embodiments, trospium isadministered at a dose of about from 1 mg/day to 100 mg/day, from about1 mg/day to 20 mg/day, from about 2 mg/day to 10 mg/day, from about 4mg/day to about 8 mg/day. In some embodiments, the concentration oftrospium in the urine is about 0.1 μg/mL to about 20 μg/mL, about 1μg/mL to about 10 μg/mL, about 2 μg/mL to about 8 μg/mL, about 3 μg/mLto about 7 μg/mL, or about 3 μg/mL to about 5 μg/mL while trospium isadministered. In some embodiments, trospium is administered continuouslyor intermittently. In some embodiments, the individual having overactivebladder experiences at least about 50% of baseline symptom relief for atleast about 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks aftertrospium administration is completed. In some embodiments, theindividual is human. In some embodiments, the individual has idiopathicoveractive bladder. In some embodiments, the individual has multiplesclerosis, Alzheimer's disease, Parkinson's disease, or has previouslyhad a stroke.

Provided herein is a method maintenance therapy for overactive bladderin an individual comprising administering trospium continuously andlocally to the bladder for at least about 24 hours on a prn (as needed)basis, wherein the individual has received a previous therapy foroveractive bladder. In some embodiments the maintenance therapycomprises administering tropism locally to the bladder for at leastabout 42 days, at least about 56 days, or at least about 84 days. Insome embodiments the prior therapy is an oral therapy. In someembodiments, the prior therapy comprises local administration oftrospium to the bladder. In some embodiments, trospium is administeredby using an intravesical delivery device. In some embodiments, trospiumis administered at a dose of about from 1 mg/day to 100 mg/day, fromabout 1 mg/day to 20 mg/day, from about 2 mg/day to 10 mg/day, fromabout 4 mg/day to about 8 mg/day. In some embodiments, the concentrationof trospium in the urine is about 0.1 μg/mL to about 20 μg/mL, about 1μg/mL to about 10 μg/mL, about 2 μg/mL to about 8 μg/mL, about 3 μg/mLto about 7 μg/mL, or about 3 μg/mL to about 5 μg/mL while trospium isadministered. In some embodiments, trospium is administered continuouslyor intermittently. In some embodiments, the individual having overactivebladder experiences at least about 50% of baseline symptom relief for atleast about 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks aftertrospium administration is completed. In some embodiments, theindividual is human. In some embodiments, the individual has idiopathicoveractive bladder. In some embodiments, the individual has multiplesclerosis, Alzheimer's disease, Parkinson's disease, or has previouslyhad a stroke.

Also provided herein is a method maintenance therapy for overactivebladder in an individual comprising administering trospium continuouslyand locally to the bladder for at least about 24 hours on a quarterlybasis, wherein the individual has received a previous therapy foroveractive bladder. In some embodiments the maintenance therapycomprises administering tropism locally to the bladder for at leastabout 42 days, at least about 56 days, or at least about 84 days. Insome embodiments the prior therapy is an oral therapy. In someembodiments, the prior therapy comprises local administration oftrospium to the bladder. In some embodiments, trospium is administeredby using an intravesical delivery device. In some embodiments, trospiumis administered at a dose of about from 1 mg/day to 100 mg/day, fromabout 1 mg/day to 20 mg/day, from about 2 mg/day to 10 mg/day, fromabout 4 mg/day to about 8 mg/day. In some embodiments, the concentrationof trospium in the urine is about 0.1 μg/mL to about 20 μg/mL, about 1μg/mL to about 10 μg/mL, about 2 μg/mL to about 8 μg/mL, about 3 μg/mLto about 7 μg/mL, or about 3 μg/mL to about 5 μg/mL while trospium isadministered. In some embodiments, trospium is administered continuouslyor intermittently. In some embodiments, the individual having overactivebladder experiences at least about 50% of baseline symptom relief for atleast about 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks aftertrospium administration is completed. In some embodiments, theindividual is human. In some embodiments, the individual has idiopathicoveractive bladder. In some embodiments, the individual has multiplesclerosis, Alzheimer's disease, Parkinson's disease, or has previouslyhad a stroke.

Trospium

Trospium is a muscarinic receptor antagonist. It is known for use in thetreatment of overactive bladder, where it is formulated for oraladministration, e.g., Sanctura™ (Allergan). As with other oralmuscarinic receptor antagonists, patients often experience dose limitingside effects or inadequate efficacy. In the present application,trospium is formulated for local delivery. It may be provided in solidor semi-solid form or in a liquid form, depending on the deliverymechanism employed, as described herein. In some embodiments, devices,and systems described herein, trospium is provided in the form of apharmaceutically acceptable salt of trospium. In some embodiments, thepharmaceutically acceptable salt of trospium is trospium chloride. Insome embodiments, other suitable form of trospium is used, including butnot limited to a polymorph, a hydrate, etc.

In some embodiments, trospium is the compound3-(2-hydroxy-2,2-diphenylacetoxy)spiro[bicyclo[3.2.1]octane-8,1′-pyrrolidin]-1′-ium chloride and anypharmaceutically-acceptable salt thereof. The chemical formula is givenin formula I.

Dosage Regimens

The following section describes various aspects (embodiments) of dosingand treatment regimens, any and all of which apply to the methodsdescribed herein.

In various embodiments, trospium is administered locally to the bladder(e.g., intravesically) in a dosage amount from about 0.075 mg/day toabout 150 mg/day, such as from about 0.15 mg/day to 150 mg/day, fromabout 1 mg/day to 100 mg/day, from about 1 mg/day to 20 mg/day, fromabout 2 mg/day to 10 mg/day, from about 4 mg/day to about 8 mg/day overthe treatment period. In some embodiments, trospium is administeredlocally to the bladder (e.g., intravesically) in a dosage amount no morethan about 60 mg/day, 40 mg/day, 20 mg/day, 15 mg/day, 10 mg/day or 8mg/day over the treatment period. In some embodiments, trospium isadministered locally to the bladder (e.g., intravesically) in a dosageamount no less than about 0.1 mg/day, 0.5 mg/day, 1 mg/day, 2 mg/day, 3mg/day, 4 mg/day.

In some embodiments, trospium is administered locally to the bladder(e.g., intravesically) of an individual for at least about 24 hours, 2days, 3 days, 4 days, 5 days, 6 days, or 7 days. In some embodiments,trospium is administered locally to the bladder (e.g., intravesically)of an individual for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15, or 16 weeks. In some embodiments, trospium isadministered locally to the bladder (e.g., intravesically) of anindividual for at least about 6 weeks, or 42 days. In some embodiments,trospium is administered locally to the bladder (e.g., intravesically)of an individual for at least about 8 weeks, or 56 days. In someembodiments, trospium is administered locally to the bladder for atleast about 12 weeks, or 84 days. In some embodiments, trospium isadministered locally to the bladder (e.g., intravesically) of anindividual for at least about 16 weeks, or 112 days. In someembodiments, trospium is administered locally to the bladder (e.g.,intravesically) of an individual for at least about 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, or 12 months. In some embodiments, trospium isadministered locally to the bladder (e.g., intravesically) of anindividual for at least about 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100days. In some embodiments, trospium is administered locally to thebladder (e.g., intravesically) of an individual for about 7 days, 14days, 21 days, 28 days, 35 days, 42 days, 49 days, 56 days, 63 days, 70days, 77 days, 84 days, 91 days, 98 days, 105 days, or 112 days.

In some embodiments, trospium is administered locally to the bladder(e.g., intravesically) of an individual for at least about 24 hours, 2days, 3 days, 4 days, 5 days, 6 days, or 7 days every one, two, three,four five or six weeks. In some embodiments, trospium is administeredlocally to the bladder (e.g., intravesically) of an individual for atleast about 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 daysevery one, two, three, four, five or six months. In some embodiments,trospium is administered locally to the bladder (e.g., intravesically)of an individual for at least about one week, two weeks, three weeks orfour weeks every one, two, three, four, five or six months. In someembodiments, trospium is administered locally to the bladder (e.g.,intravesically) of an individual for at least about five weeks or sixweeks every two, three, four, five or six months.

In some embodiments, trospium is administered locally (e.g.,intravesically) into the individual's bladder at a mean average amountof from 1 mg/day to 100 mg/day, for example, from 1 mg/day to 20 mg/day,from 2 mg/day to 10 mg/day, from 4 mg/day to about 8 mg/day for up toabout 7, 14, 21, 28, 35, 42 days, 49 days, 56 days, 63 days, 70 days, 77days, 84 days, 91 days, 98 days, 105 days, or 112 days. In someembodiments, trospium is administered locally (e.g., intravesically)into the individual's bladder at a mean average amount of from 1 mg/dayto 100 mg/day, for example, from 1 mg/day to 20 mg/day, from 2 mg/day to10 mg/day, from 4 mg/day to about 8 mg/day for up to about 6, 7, 8, 9,10, 11, or 12 months.

In some embodiments, trospium is administered locally (e.g.,intravesically) into the individual's bladder at a mean average amountof about 10 mg/day for about 40-45 days (such as about 42 days). In someembodiments, trospium is administered locally (e.g., intravesically)into the individual's bladder at a mean average amount of about 10mg/day for about 80-87 days (such as about 84 days). In someembodiments, trospium is only administered once.

In some embodiments, the concentration of trospium in the urine is aboutor at least about 0.01, 0.05, 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, or 8 μg/mLwhile trospium is administered. In some embodiments, the concentrationof trospium in the urine is about 2-3 μg/mL, about 3-4 μg/mL, about 4-5μg/mL, about 5-6 μg/mL, or about 6-7 μg/mL while trospium isadministered. In some embodiments, the concentration of trospium in theurine is about 0.01 to about 100 μg/mL, for example, about 0.1 μg/mL toabout 20 μg/mL, about 1 μg/mL to about 10 μg/mL, about 2 μg/mL to about8 μg/mL, about 3 μg/mL to about 7 μg/mL, or about 3 μg/mL to about 5μg/mL while trospium is administered. In some embodiments, the averageconcentration of trospium in the urine is at least about 0.01, 0.1, 1,2, 3, 4, 5, 6, 7, 8, 9, or 10 μg/mL while trospium is administered. Insome embodiments, the average concentration of trospium in the urine isabout 0.01 to about 100 μg/mL, about 0.1 μg/mL to about 20 μg/mL, about1 μg/mL to about 10 μg/mL, or about 2 μg/mL to about 8 μg/mL, about 3μg/mL to about 7 μg/mL, or about 3 μg/mL to about 5 μg/mL while trospiumis administered. In some embodiments, the plasma concentration oftrospium is less than about 2, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3,0.2, or 0.1 ng/ml. In some embodiments, the plasma concentration oftrospium is less than about 0.7 ng/ml. In some embodiments, the plasmaconcentration of trospium not detectable.

In some embodiments, trospium is administered to the bladder via anintravesical delivery device. In some embodiments, the device containsan amount of about 100 mg to 2000 mg trospium (such as about 200 mg toabout 1600 mg, about 400 mg to about 1200 mg, about 600 mg to about 1000mg, about 700 mg to about 900 mg, or about 850 mg trospium). In someembodiments, the device is kept in the individual for at least aboutone, two, three, four, five or six weeks. In some embodiments, thedevice is kept in the individual for at least about 8, 10, or 12 weeks.In some embodiments, the device contains an amount of about 850 mgtrospium and is kept in the individual for about 42 days. In someembodiments, the device contains an amount of about 850 mg trospium andis kept in the individual for about 84 days.

In some embodiments, the method comprises a maintenance therapycomprising administering an effective amount of trospium locally (e.g.,intravesically) into the individual's bladder periodically following aprior therapy. In some embodiments, the maintenance therapy comprisesadministering trospium as needed. In some embodiments, the maintenancetherapy comprises administering trospium monthly, bi-monthly orquarterly. In some embodiments, the maintenance therapy comprisesadministering trospium no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,or 12 times per year. In some embodiments, the maintenance therapycomprises administering trospium on a schedule agreed by the individualand a doctor. In some embodiments, the maintenance therapy comprisesadministering trospium when a symptom of overactive bladder isanticipated to return. In some embodiments, the maintenance therapycomprises administering trospium upon symptom recurrence, for example,when at least an about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90%recurrence in baseline symptom occurs. In some embodiments, themaintenance period comprises administering trospium for at least about24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days. In someembodiments, the maintenance period comprises administering trospium forat least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16weeks. In some embodiments, the maintenance therapy comprisesadministering trospium for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, or 12 months. In some embodiments, the maintenance therapy comprisesadministering trospium for at least about 10, 20, 30, 40, 50, 60, 70,80, 90, or 100 days. In some embodiments, the maintenance therapycomprises administering trospium for about 7 days, 14 days, 21 days, 28days, 35 days, 42 days, 49 days, 56 days, 63 days, 70 days, 77 days, 84days, 91 days, 98 days, 105 days, or 112 days.

In some embodiments, the prior therapy comprises administering anantimuscarinic agent. In some embodiments, the antimuscarinic agent islocally administered into the bladder (e.g. intravesically) of theindividual. In some embodiments, the antimuscarinic agent is orallyadministered a local treatment into the individual. In some embodiments,the antimuscarinic agent is trospium. In some embodiments, the priortherapy comprises administering an anticholinergic agent. In someembodiments, the prior therapy comprises administering trospium locallyto the bladder for about 42 or about 56 days.

In some embodiments, the maintenance therapy is initiated immediatelyafter or within 24 hours of the completion of the prior therapy. In someembodiments, the maintenance therapy is initiated at least about 1, 2,3, 4, 5, 6, or 7 days after the completion of the prior therapy. In someembodiments, the maintenance therapy is initiated at least about 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks after the completion of theprior therapy. In some embodiments, the maintenance therapy is initiatedat least about 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months after thecompletion of the prior therapy.

In some embodiments, the concentration of trospium in the urine is atleast about 0.01, 0.05, 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, or 8 μg/mL duringthe prior therapy and/or the maintenance therapy period. In someembodiments, the concentration of trospium in the urine is about 0.01μg/mL to about 100 μg/mL, for example, about 0.1 μg/mL to about 20μg/mL, about 1 μg/mL to about 10 μg/mL, about 2 μg/mL to about 8 μg/mL,about 3 μg/mL to about 7 μg/mL during the prior therapy and/or themaintenance period. In some embodiments, the average concentration oftrospium in the urine is at least about 0.01, 0.1, 1, 2, 3, 4, 5, 6, 7,8, 9, or 10 μg/mL during the prior therapy and/or the maintenancetherapy period. In some embodiments, the average concentration oftrospium in the urine is about 0.01 μg/mL to about 100 μg/mL, about 0.1μg/mL to about 20 μg/mL, about 1 μg/mL to about 10 μg/mL, or about 3μg/mL to about 8 μg/mL during the prior therapy and/or the maintenancetherapy period.

In some embodiments, trospium is administered continuously. In someembodiments, trospium is administered intermittingly.

In some embodiments, trospium is administered via an intravesicaldevice, wherein the intravesical device dwells in the bladder for aperiod of time, such as at least about 24 hours, for example, for atleast about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks. In someembodiments, the intravesical device dwells in the bladder for at leastabout 1, 2, 3, 4, 5, or 6 months. In various embodiments, theintravesical device may release trospium continuously or intermittentlyto achieve a concentration of trospium in the bladder that produces asustained, therapeutically effective concentration of trospium over aperiod from about 24 hours to about 6 months, for example from about 24hours to 7 days, from about 24 hours to two weeks, from about 24 hoursto four weeks, from about 24 hours to six weeks, from about 24 hours toeight weeks, from about 24 hours to ten weeks, from about 24 hours totwelve weeks, etc. In some embodiments, trospium is administered to thebladder for about 42 days. In some embodiments, trospium is administeredto the bladder for about 56 days or 112 days.

In some embodiments, average total daily urinary recovery of trospiumduring the device indwelling time is at least about 0.1, 0.5, 1, 1.5, 2,2.5, or 3 mg/day. In some embodiments, average total daily urinaryrecovery of trospium during the device indwelling time is no more about30, 18, 15, 12, 10, 9, or 8 mg/day. In some embodiments, average totaldaily urinary recovery of trospium during the device indwelling time isabout 0.1 mg/day to about 30 mg/day, about 1 mg/day to about 25 mg/day,about 2 mg/day to about 10 mg/day, about 3 mg/day to about 9 mg/day.

Patient Populations

The individuals treated with the methods described herein can be amammal. In some embodiments, the individual is human.

In some embodiments, the individual has idiopathic overactive bladder.

In some embodiments, the individual has received a previous therapy foroveractive bladder. In some embodiments, the individual is refractory tothe previous therapy. In some embodiments, the individual hasrecalcitrant overactive bladder. In some embodiments, the individual hassevere overactive bladder. In some embodiments, the individual does notrespond to the previous therapy. In some embodiments, the individualprogresses on the previous therapy. In some embodiments, the individualhas a recurrence of baseline symptoms upon the completion of the priortherapy, for example, wherein the individual has at least an about 10%,20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% recurrence in baselinesymptoms. In some embodiments, the prior therapy is an oral therapy. Insome embodiments, the prior therapy is a local therapy. In someembodiments, the prior therapy comprises administering an antimuscarinicagent. In some embodiments, the agent is selected from the groupconsisting of Botox®, VESIcare® (solifenacin succinate) and Detrol® LA(tolterodine tartrate). In some embodiments, the prior therapy comprisesadministering an anticholinergic agent.

In some embodiments, the individual has not received a previous therapyfor overactive bladder.

In some embodiments, the individual is not eligible for an oral therapy.For example, the individual cannot tolerate side effects from thetherapy. In some embodiments, the individual is old or frail. In someembodiments, the oral therapy comprises an anticholinergic agent. Insome embodiments, the oral therapy comprises an antimuscarinic agent. Insome embodiments, the agent is selected from the group consisting ofBotox®, VESIcare® (solifenacin succinate) and Detrol® LA (tolterodinetartrate).

In some embodiments, the individual has a neurological condition. Insome embodiments, the neurological condition is multiple sclerosis. Insome embodiment, the neurological condition is Parkinson's disease. Insome embodiments, the neurological condition is Alzheimer's disease. Insome embodiments, the individual has had a stroke.

In some embodiments, the individual has symptoms of overactive bladderwith a predominant urge component, for example, wherein more than 50% ofthe symptoms of overactive bladder are associated with urgency (asopposed to frequency). In some embodiments, the individual has symptomsof overactive bladder with a predominant urge component for at leastabout 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks. In someembodiments, the individual has symptoms of overactive bladder with apredominant urge component for at least about 3, 4, 5, 6, 7, 8, 9, 10,11, or 12 months. In some embodiments, the individual has about four,five, six, seven, eight or more voids per 24 hours. In some embodiments,the individual has at least about 2, 3, 4, 5, or 6 incontinence episodesassociated with urgency in a 3-day diary. In some embodiments, theindividual has at least one, two or three episodes that occur each 24hours or per day.

In some embodiments, the individual has urinary incontinence or urgeincontinence.

In some embodiments, the individual has a post-void residual volume(PVR) of less than about 300 mL (such as less than about 300 mL, 250 mL,200 mL, 150 mL, or 100 mL).

In some embodiments, the individual is a female. In some embodiments,the individual is a male.

In some embodiments, the individual is about 40 to about 70 years old.In some embodiments, the individual is at least about 40, 45, 50, 55,60, 65, or 70 years old. In some embodiments, the individual is no morethan about 70, 65, 60, 55, 50, 45, or 40 years old.

Overactive Bladder

In some embodiments, the overactive bladder is associated with aneurological condition. In some embodiments, the neurological conditionis multiple sclerosis. In some embodiment, the neurological condition isParkinson's disease. In some embodiments, the neurological condition isAlzheimer's disease. In some embodiments, the neurological condition isa previous stroke.

In some embodiments, the overactive bladder is not associated with aneurological condition.

Endpoints

In some embodiments, the methods provided herein prolong symptom relieffor an individual having overactive bladder, comprising deliveringtrospium locally to the bladder for at least about 24 hours. In someembodiments, the individual experience at least about 10%, 20%, 30%,40%, 50%, 60%, 70%, 80%, or 90% of baseline symptom relief during orafter the completion of the administration of trospium. In someembodiments, symptom relief comprises a reduction in urgency and/orfrequency. In some embodiments, symptom relief comprises a reduction inan aberrant urge. In some embodiments, urgency and/or frequency isreduced by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%from baseline during or after the completion of the administration oftrospium. In some embodiments, the symptom relief comprises a reductionin urinary incontinence and/or urge incontinence (e.g., dailyincontinence episodes or incontinence episodes within 3 days). In someembodiments, urinary incontinence and/or urge incontinence (e.g., dailyincontinence episodes or incontinence episodes within 3 days) is reducedby at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% frombaseline symptom during or after the completion of the administration oftrospium. In some embodiments, the symptom relief is prolonged for atleast about 1, 2, 3, 4, 5, 6, or 7 days after the completion of theadministration of trospium. In some embodiments, the symptom relief isprolonged for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12weeks after the completion of the administration of trospium. In someembodiments, the symptom relief is prolonged for at least about 3, 4, 5,6, 7, 8, 9, 10, 11, or 12 months after the completion of theadministration of trospium.

In some embodiments, the individual has a reduction in daily micturitionepisodes during or after the completion of the administration oftrospium. In some embodiments, daily micturition episodes are reduced byat least about 2.5%, 5%, 7.5%, or 10% from baseline symptom during orafter the completion of the administration of trospium. In someembodiments, the reduction is prolonged for at least about 1, 2, 3, 4,5, 6, or 7 days after the completion of the administration of trospium.In some embodiments, the reduction is prolonged for at least about 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks after the completion of theadministration of trospium. In some embodiments, the reduction isprolonged for at least about 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 monthsafter the completion of the administration of trospium.

In some embodiments, the individual has an increase in voided volume permicturition during or after the completion of the administration oftrospium. In some embodiments, the increase in voided volume permicturition is at least about 2.5%, 5%, 7.5%, 10%, 20%, 25%, 30%, 35%,or 40% from baseline symptom during or after the completion of theadministration of trospium. In some embodiments, the increase isprolonged for at least about 1, 2, 3, 4, 5, 6, or 7 days after thecompletion of the administration of trospium. In some embodiments, theincrease is prolonged for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, or 12 weeks after the completion of the administration of trospium.In some embodiments, the increase is prolonged for at least about 3, 4,5, 6, 7, 8, 9, 10, 11, or 12 months after the completion of theadministration of trospium.

In some embodiments, provided herein is a method for improving thequality of life of an individual comprising administering an effectiveamount of trospium locally to the bladder for at least about 24 hours.In some embodiments, the quality of life score of the individual isincreased. In some embodiments, the individual has an improved qualityof life score at least about 24 hours after the local administration oftrospium is completed compared with prior the quality of life scoreprior to local treatment with trospium. In some embodiments, the qualityof life score includes a score based upon the frequency with which theindividual has experienced one or more events over a period of time, forexample, none of the time, a little of time, some of the time, a goodbit of the time, most of the time, and all of the time. In someembodiments, the event comprises being bothered by a sudden urge tourinate with little or no warning. In some embodiments, the eventcomprises being bothered by an accidental loss of small amounts ofurine. In some embodiments, the event comprises being bothered bynighttime urination. In some embodiments, the event comprises beingbothered by waking up at night because he/she had to urinate. In someembodiments, the event comprises being bothered urine loss associatedwith a strong desire to urinate. In some embodiments, the quality oflife score of the individual is improved by about 10%, 20%, 30%, 40%,50%, 60% 70% or 80% after local administration of trospium. In someembodiments, the quality of life score of the individual is improved forat least 1, at least 2, at least 3, at least 4, at least 5, at least 6,at least 7, at least 8, at least 10, at least 11, or at least 12 weeksafter local trospium administration is completed.

In some embodiments, provided herein is a method for improving thequality of life score of an individual comprising administering aneffective amount of trospium locally to the bladder for at least about24 hours. In some embodiments, the individual has an improved quality oflife score at least about 24 hours after the local administration oftrospium is completed compared with prior the quality of life scoreprior to local treatment with trospium. In some embodiments, the qualityof life score includes a score based upon the frequency with which theindividual has experienced one or more events over a period of time, forexample, none of the time, a little of time, some of the time, a goodbit of the time, most of the time, and all of the time. In someembodiments, the event comprises being bothered by a sudden urge tourinate with little or no warning. In some embodiments, the eventcomprises being bothered by an accidental loss of small amounts ofurine. In some embodiments, the event comprises being bothered bynighttime urination. In some embodiments, the event comprises beingbothered by waking up at night because he/she had to urinate. In someembodiments, the event comprises being bothered urine loss associatedwith a strong desire to urinate. In some embodiments, the quality oflife score of the individual is improved by about 10%, 20%, 30%, 40%,50%, 60% 70% or 80% after local administration of trospium. In someembodiments, the quality of life score of the individual is improved forat least 1, at least 2, at least 3, at least 4, at least 5, at least 6,at least 7, at least 8, at least 10, at least 11, or at least 12 weeksafter local trospium administration is completed.

In some embodiments, provided herein is a method of reducing the botherassociated with bladders symptoms in an individual comprising deliveringtrospium to the bladder of an individual for at least about 24 hours. Insome embodiments, the bother score of the individual is reduced. In someembodiments, the bother score is reduced at least about 24 hours afterthe local administration of trospium is completed compared with prior tolocal treatment with trospium. n some embodiments, the quality of lifescore can include a score based upon the frequency with which theindividual has experienced one or more events over a period of time, forexample, none of time, a little of time, some of the time, a good bit ofthe time, most of the time, and all of the time. In some embodiments,the event comprises planning escape routes to restrooms in publicplaces. In some embodiments, the event comprises bladder symptomsaffecting the frequency at which the individual's bladder symptoms makethe individual feel like there is something wrong with him/her. In someembodiments, the event comprises bladder symptoms interfering withhis/her ability to get a good night's rest. In some embodiments, theevent comprises bladder symptoms that make the individual frustrated orannoyed about the amount of time he/she spent in the restroom. In someembodiments, the event comprises bladder symptoms that make theindividual avoid activities away from restrooms (e.g., walking, running,hiking). In some embodiments, the event comprises bladder symptoms thatawaken the individual during sleep. In some embodiments, the eventcomprises bladder symptoms that cause the individual to decrease his orher physical activities (exercising, sports, etc.). In some embodiments,the event comprises a bladder symptoms that cause the individual to haveproblems with his/her partner or spouse. In some embodiments, the eventcomprises bladder symptoms that make the individual uncomfortable whiletraveling with others because of needing to stop for a restroom. In someembodiments, the event comprises bladder symptoms that affect theindividual's relationships with family and friends. In some embodiments,the event comprises embarrassment caused by the individual's bladdersymptoms. In some embodiments, the event comprises when the individual'sbladder symptoms cause the individual to locate the closest restroomupon arrival at a new place. In some embodiments, the bother score ofthe individual is improved by about 10%, 20%, 30%, 40%, 50%, 60% 70% or80% after local administration of trospium. In some embodiments, thebother score of the individual is improved for at least 1, at least 2,at least 3, at least 4, at least 5, at least 6, at least 7, at least 8,at least 10, at least 11, or at least 12 weeks after local trospiumadministration is completed.

In some embodiments, the quality of life score [i.e., health-relatedquality of life (HRQL) transformed score] and the bother score (i.e.symptom severity transformed score) are calculated from subject'sself-evaluations via a questionnaire. Exemplary questionnaires are shownin FIGS. 13-14. Evaluations can be made prior to (such as immediatelyprior to) the trospium administration to establish a baseline.Evaluations can also be made at different time points during or afterthe administration of trospium.

For example, the quality of life score can be calculated from FIG. 14raw score as follows, where the raw score was the total score from thevalues of items 1-13. Quality of life score=(Highest possiblescore−Actual raw score)/Possible raw score range×100 where the highestpossible score was 78 and the possible raw score range was 65. Note thathigher quality of life score values are indicative of better quality oflife.

The bother score can be calculated from FIG. 13 raw score as follows,where the raw score was the total score from the values of items 1-6.Bother score=(Actual raw score−lowest possible raw score)/Possible rawscore range×100, where the lowest possible raw score=6, and the possibleraw score range was 30. Note that higher bother score values areindicative of greater symptom severity or bother and lower scoresindicate minimal symptom severity.

In some embodiments, the trospium is delivered via an intravesicaldevice described herein. In some embodiments, the individual has a hightolerability to the device (for example, less than about 30%, 20%, 15%,10%, 5% or 2% of the individuals require removal of the device prior tothe completion of the scheduled treatment.

In some embodiments, the method does not cause a significant level ofadverse events in the individual. Exemplary adverse events includeurinary tract infection (UTI), bladder pain, hematuria, sinusitis andbladder discomfort. In some embodiments, less than about 50%, 40%, 30%,25%, or 20% of the individuals develop an UTI during the treatmentperiod. In some embodiments, less than about 50%, 40%, 30%, 25%, or 20%of the individuals develop bladder pain during the treatment period. Insome embodiments, less than about 50%, 40%, 30%, 25%, or 20% of theindividuals develop hematuria during the treatment period. In someembodiments, less than about 50%, 40%, 30%, 25%, or 20% of theindividuals develop sinusitis during the treatment period. In someembodiments, less than about 50%, 40%, 30%, 25%, or 20% of theindividuals develop bladder discomfort during the treatment period.

In some embodiments, the bladder post-void residual volume (PVR) in theindividual is reduced by at least about 5%, 10%, 15%, 20%, 25%, 30%,35%, or 40% after the administration of trospium. In some embodiments,the reduction is observed within about 7 days, 21 days or 35 days afteradministration of trospium.

Delivery

I. Intravesical Devices

a. Device Shape

In some embodiments, the methods provided herein comprise locallydelivering to the bladder an effective amount of trospium using anintravesical device. In some embodiments, the intravesical devicecomprises a deployment shape and a retention shape. For example, thedevice may be elastically deformable between a relatively straightenedor uncoiled shape suited for insertion through a lumen (e.g., theurethra) into the bladder of the individual (the deployment shape) and aretention shape suited to retain the device within the bladder. For thepurposes of this disclosure, terms such as “relatively expanded shape,”“relatively higher-profile shape,” or “retention shape” generally denoteany shape suited for retaining the device in the intended implantationlocation, including but not limited to a pretzel shape or other coiledshape (e.g., comprising bi-oval or overlapping coils) that is suited forretaining the device in the bladder. The retention shape provides thatthe device resists becoming entrained in urine and excreted when theindividual voids. Similarly, terms such as “relatively lower-profileshape” or “deployment shape” generally denote any shape suited fordeploying the drug delivery device into the body, for example thebladder, including, but not limited to, including a linear or elongatedshape that is suited for deploying the device through the workingchannel of catheter, cystoscope, or other deployment instrumentpositioned in the urethra or in the bladder, for example, a suprapubiccystostomy or suprapubic catheter (also known as a vesicostomy orepicystostomy) used to drain urine from the bladder in individuals withobstruction of normal urinary flow. In embodiments, the drug deliverydevice may naturally assume the relatively expanded shape and may bedeformed, either manually or with the aid of an external apparatus, intothe relatively lower-profile shape for insertion into the body. Forexample, the external apparatus may be an inserter configured fortransurethral insertion. Once deployed the intravesical device mayspontaneously or naturally return to the initial, relatively expandedshape for retention in the body. In some embodiments, the device behaveslike a spring, deforming in response to a compressive load (e.g.,deforming the device into a deployment shape) but spontaneouslyreturning to a retention shape once the load is removed.

In some embodiments, the shape changing functionality of theintravesical device described in the preceding paragraph may be providedby including a shape retention frame (i.e., a “retention frame”) in thedevice, such as those disclosed in published applicationsUS2012/0203203, US2013/0158675, US2015/0360012, US20150165177,US2015/0165178, US20160199544, WO2014/145638, WO2015200752, andWO2011/031855, which are incorporated herein by reference. In someembodiments, the device may include a retention frame lumen in which theretention frame, which may be an elastic wire, e.g., a superelasticalloy such as nitinol, is secured. The retention frame may be configuredto return spontaneously to a retention shape, such as a “pretzel” shapeor another coiled shape, such as those disclosed in the applicationspreviously incorporated. In particular, the retention frame may retainthe device in the body, such as in the bladder. The retention shapeprovides that the device resists becoming entrained in urine andexcreted when the individual voids. For example, the retention frame mayhave an elastic limit and modulus that allows the device to beintroduced into the body in a relatively lower-profile shape, permitsthe device to return to the relatively expanded shape once inside thebody, and impedes the device from assuming the relatively lower-profileshape within the body in response to expected forces, such as thehydrodynamic forces associated with contraction of the detrusor muscleand urination. Thus, the device may be retained in the individual'sbladder once deployed, limiting or preventing accidental expulsion.

In some other embodiments, the shape changing functionality of theintravesical device may be provided by forming the device housing atleast in part of a thermally shape set elastic polymer, for example, asdescribed in WO 2016/172704.

The material used to form the device body (i.e., the housing), at leastin part, may be elastic or flexible to permit moving the device betweendeployment and retention shapes. When the device is in the retentionshape, the retention frame portion may tend to lie inside the drugreservoir portion, although the retention frame portion can bepositioned inside, outside, above, or below the drug reservoir portionin other cases. The material used to form the device body may be waterpermeable so that solubilizing fluid (e.g., urine) can enter the drugreservoir portion to solubilize the non-liquid forms of trospium,chemotherapeutic agent, immunomodulating agent, additional therapeuticagent, functional agent, or combination thereof contained in the drugreservoir once the device is deployed into the bladder. For example,silicone or another biocompatible elastomeric material may be used. Inother embodiments, the device body may be formed, at least in part, of awater-impermeable material.

In some embodiments, the device body is made of an elastic,biocompatible polymeric material. The material may be non-resorbable orresorbable. Example non-resorbable materials include synthetic polymersselected from poly(ethers), poly(acrylates), poly(methacrylates),poly(vinyl pyrrolidones), poly(vinyl acetates), poly(urethanes),celluloses, cellulose acetates, poly(siloxanes), poly(ethylene),poly(tetrafluoroethylene) and other fluorinated polymers, andpoly(siloxanes). Example resorbable materials, specificallybiodegradable or bioerodible polymers, include synthetic polymersselected from poly(amides), poly(esters), poly(ester amides),poly(anhydrides), poly(orthoesters), polyphosphazenes, pseudo poly(aminoacids), poly(glycerol-sebacate), poly(lactic acids), poly(glycolicacids), poly(lactic-co-glycolic acids), poly(caprolactones),poly(caprolactone) (PC) derivatives, amino alcohol-based poly(esteramides) (PEA) and poly(octane-diol citrate) (POC), and other curablebioresorbable elastomers. PC-based polymers may require additionalcross-linking agents such as lysine diisocyanate or2,2-bis(e-caprolacton-4-yl)propane to obtain elastomeric properties.Copolymers, mixtures, and combinations of the above materials also maybe employed.

In some embodiments, the device body comprises silicone, thermoplasticpolyurethane, ethyl vinyl acetate (EVA), or a combination thereof. Insome embodiments, the device body comprises two different thermoplasticmaterials, one of which is a hydrophilic thermoplastic polyurethane andis drug permeable, with the other being drug-impermeable. The drugimpermeable material may be a selected from the group consisting ofhydrophilic polyurethane, hydrophilic polyesters, and hydrophilicpolyamides. The device body may comprise an annular tube formed by anextrusion or coextrusion process, using one or more these materials, asdescribed in U.S. Publication 2016/0310715, which is incorporated hereinby reference.

b. Drug Core/Payload

In embodiments in which trospium is delivered from an intravesical drugdelivery device, the composition may be housed in the device in variousforms, which may depend on the particular mechanism by which the devicecontrollably releases the composition into fluid (e.g., urine) in thebladder. In some embodiments, the composition is provided in a solid,semi-solid, or other non-liquid form, which advantageously mayfacilitate stable storage of the composition before the device is usedand advantageously may enable the composition payload of the device tobe stored in smaller volume than would be possible if the compositionwere housed in the form of a liquid solution. In some embodiments, thenon-liquid form is selected from tablets, granules, pellets, powders,semisolids (e.g., an ointment, cream, paste, or gel), capsules, andcombinations thereof. In one embodiment, the composition is in the formof a plurality of tablets, such as mini-tablets described in U.S. Pat.No. 9,757,546.

For example, trospium, may take such forms as suspensions, solutions,colloids, micelles, or emulsions in oily or aqueous vehicles, and maycontain formulatory agents such as suspending, stabilizing and/ordispersing agents. Alternatively, the active ingredients may be inpowder form, obtained by aseptic isolation of sterile solid or bylyophilization from solution, for constitution with a suitable vehicle,e.g., sterile, pyrogen-free water, before use.

In one embodiment, trospium is formulated with one or more excipientsthat include a viscosity enhancing agent to control release of trospiumfrom a release aperture in the device housing. In another embodiment,the device reservoir includes both trospium and a viscosity enhancingagent, but they are not co-formulated and instead are provide indiscrete regions within the reservoir, e.g., as separate tablets.Suitable viscosity enhancing agents, including but not limited topolyethylene oxide (PEO), are known in the pharmaceutical arts. In somevariations of the embodiment, the viscosity enhancing agent may beprovided, e.g., formulated, with urea or another osmotic agent.

In one embodiment, trospium is delivered to the bladder of theindividual with a solubility enhancing agent. In an embodiment, thesolubility enhancing agent is urea. In one embodiment, the urea isprovided in a tablet or other solid form and loaded with trospium in thedrug reservoir of an intravesical drug delivery device. The urea mayalso function, depending on the device, as an osmotic agent tofacilitate generation of an osmotic pressure in a drug reservoir. In aparticular embodiment, trospium and the osmotic agent are configured asseparate payloads (i.e., powders, tablets, or other solid forms)positioned within different regions of the drug reservoir as describedin PCT WO 2015/026813 (Lee et al.) which is incorporated by referenceherein.

In some embodiments, the device may comprise a drug reservoir lumen. Insome of these embodiments, each drug reservoir lumen may hold one orseveral drug tablets or other solid drug units. In one embodiment, thedevice holds from about 10 to 100 cylindrical drug tablets, such asmini-tablets, among a number of discrete drug reservoir lumens. Incertain embodiments, the mini-tablets may each have a diameter of about1.0 to about 3.3 mm, such as about 1.5 to about 3.1 mm, and a length ofabout 1.5 to about 4.7 mm, such as about 2.0 to about 4.5 mm. In someother embodiments, the drug reservoir lumen contains a powder form orgranulated form of trospium.

In some embodiments, the intravesical device contains and releases afunctional agent along with trospium. The functional agent mayfacilitate release of the drug from the device and/or may facilitatestabilization (i.e. retardation of degradation) of trospium in urine inthe bladder. For example, the functional agent may include ananti-protease if proteolytic degradation of trospium in urine is aconcern.

c. Drug Housing

The release of trospium from the intravesical devices described hereinmay be driven and controlled by different mechanisms of action. Invarious embodiments, the drug may be released from the intravesical drugdelivery device by diffusion through a wall of the drug housing, bydiffusion through one or more defined apertures in a wall of the drughousing, by osmotic pressure through an aperture in the drug housing, byosmotic pressure through one or more transiently formed microchannels,by erosion of a drug formulation in contact with urine in the bladder,or by a combination thereof. In some embodiments, drug release iscontrolled by drug diffusion through/from a drug-permeable polymer ormatrix component defining part of the device housing. In one embodiment,the device includes a drug-permeable polymer component.

The size of the housing, including the thickness of the wall, may beselected based on the volume of drug (and functional agent, if any)formulation(s) to be contained, the desired rate of delivery of the drugfrom the device body/housing, the intended site of implantation of thedevice within the body, the desired mechanical integrity for the device,the desired release rate or permeability to water and urine, the desiredinduction time before onset of initial release, and the desired methodor route of insertion into the body, among other factors. In embodimentsin which the housing is a tube, the tube wall thickness may bedetermined based on the mechanical properties and water permeability ofthe tube material, as a tube wall that is too thin may not havesufficient mechanical integrity while a tube wall that is too thick mayexperience an undesirably long induction time for initial drug releasefrom the device and/or may not have sufficient flexibility to permitdelivery through a urethra or other narrow body lumen.

In some embodiments, the housing may include an elongated, annular tubehaving an inner diameter from about 2 mm to about 5 mm. The drug, andfunctional agent if any, may be solid tablets having a diametersubstantially the same as the inner diameter of the elongated annulartube. In some embodiments, the housing holds one or more first units(e.g., tablets) comprising a drug and one or more second units (e.g.,tablets) comprising a functional agent which facilitates release of thedrug and/or which facilitates stabilization of trospium in urine in thebladder. One or more of the first unit tablets may fill a length fromabout 1 cm to about 3 cm of the lumen of the tube, and one or more ofthe second unit tablets may fill a length from about 10 cm to about 15cm of the lumen of the tube. In one embodiment, the ratio of volume ofthe first unit(s) to volume of the second unit(s) is from about 0.05 toabout 0.5. Other lengths and ratios of the tablet payloads areenvisioned.

In some embodiments, the housing may be an elongated, annular tubehaving a wall thickness from 0.1 to 0.4 mm, such as a wall thickness of0.2 mm. The housing material may comprise one or more biocompatibleelastomers. The housing material may be selected such that the housinghas a durometer from 25 A to 80 A, such as 25 A, 50 A, 65 A, 70 A, or 80A.

In various embodiments, the intravesical device may release the drugcontinuously or intermittently to achieve a concentration of the drug inthe bladder that produces a sustained, therapeutically effectiveconcentration of the drug in urine in the bladder as described in themethods provided herein. In certain embodiments, the intravesical devicemay release trospium in an amount of from 1 mg/day to 1000 mg/day, forexample from 20 mg/day to 300 mg/day or from 25 mg/day to 300 mg/day. Incertain embodiments, these release rates are provided over a treatmentperiod as described herein. In certain embodiments, these release ratesare provided over a treatment period from 14 days to 21 days.

d. Osmotic and Diffusion Systems

Following in vivo deployment, the device releases trospium. Release mayoccur, as described above, due to an osmotic pressure gradient betweenthe interior and exterior of the device, the drug passing through one ormore orifices or passing pores in the device under the force of osmoticpressure. Release may also occur by diffusion, whereby the drug passesthrough one or more orifices or passing pores in the device and/orthrough a drug-permeable wall of the device, due to a drug concentrationgradient between the interior and exterior of the device. Combinationsof these release modes within a single device are possible, and in someembodiments are preferred in order to achieve an overall drug releaseprofile not readily achievable from either mode individual.

In some embodiments in which the device comprises a drug in a solidform, elution of drug from the device occurs following dissolution ofthe drug within the device. Bodily fluid enters the device, contacts thedrug and solubilizes the drug, and thereafter the dissolved drugdiffuses from the device or flows from the device under osmotic pressureor via diffusion. This “dissolved drug” may include micro- and nanoscaleparticulates of the drug in suspension that remain following substantialdissolution of the solid form of the drug and are also able to bereleased from the device, e.g., through an aperture in the devicehousing. For example, the drug may be solubilized upon contact withurine in the bladder. In certain embodiments, a water permeable wallportion of the housing is permeable to the drug in aqueous solution,such that solubilized drug is released via the wall portion, alsoreferred to herein as “trans-wall diffusion.” After the device isdeployed in the individual's bladder, urine permeates through the wall,enters the reservoir, and solubilizes trospium, and the functional agentif present. In some embodiments, the drug then diffuses directly throughthe wall at a controlled rate, due to a drug concentration gradientbetween the interior and the exterior of the device. For example, thehousing and/or any water or drug permeable wall portions may besilicone, a thermoplastic polyurethane, ethylene-co-vinyl acetate (EVA),or a combination thereof.

In some embodiments, the intravesical device includes (i) a body thatcomprises a wall bounding a reservoir defined within the body, whereinthe wall has a preformed through-hole, and comprises a water-permeableportion, and the body includes an elastic portion; (ii) a drugformulation, which comprises a trospium, disposed within the reservoir;and (iii) a restraining plug closing off an opening of the body andcontacting the elastic portion of the body, wherein the opening is influid communication with the reservoir, wherein the water-permeableportion of the wall is configured to permit water to enter the deviceand contact the drug formulation in the reservoir, and wherein releaseof the trospium from the device is controlled by (a) release of thetrospium through the preformed through-hole in the wall, and (b) releaseof the trospium through the transient formation of one or moremicrochannels between the elastic portion of the body and therestraining plug, extending to the opening, upon the generation withinthe reservoir of a hydrostatic pressure effective to form the one ormore microchannels. The drug formulation may be in the form of pluralityof tablets, and the body may be in the form of a silicone tube. Theseembodiments are further described in PCT/US18/16463, which isincorporated herein by reference.

In a first aspect, as shown in FIGS. 1A-1D, the drug delivery devices 50described herein include one or more restraining plugs 56 in contactwith the elastic portion(s) 54 of the device body 52, to permit drugrelease via the distal opening(s) of the device body, as described inU.S. Patent Application Publication 2016/0008271 to Lee, which isincorporated by reference herein in relevant part. However, in contrastto the no-orifice (i.e., no predefined aperture system) of U.S. PatentApplication Publication 2016/0008271 to Lee, in certain embodiments, asshown in FIGS. 2 and 3A, the devices include at least one preformedthrough-hole (i.e., orifice) 66 disposed in a wall of the device body52.

Thus, in certain embodiments, as shown in FIGS. 1-4, a drug deliverydevice 50 includes a body 52 that has a wall bounding a reservoir 60defined within the body 52, the wall having at least one preformedthrough-hole 66 disposed therein and including a water-permeable portion64, the body 52 including an elastic portion 54; a drug formulation 58which contains a drug, the drug formulation 58 being disposed within thereservoir 60; and at least one restraining plug 56 closing off anopening of the body 52 and contacting the elastic portion 54 of the body52, the opening being in fluid communication with the reservoir 60. Thewater-permeable portion 64 of the wall is configured to permit water toenter the drug delivery device 50 and contact the drug formulation 58located in the reservoir 60 and release of the drug 58 from the device50 is controlled by at least one of (i) release of the drug 58 throughthe at least one preformed through-hole 66 (i.e., aperture, orifice) inthe wall, and (ii) release of the drug through the transient formationof one or more microchannels 62 between the elastic portion 54 of thebody 52 and the at least one restraining plug 56, extending to theopening, upon the generation of a hydrostatic pressure effective to formthe one or more microchannels 62. In these embodiments, the restrainingplugs 56 may be partially or wholly unsealed at the distal end openingsof the device 50. Such systems have been found to provide consistent andreproducible drug release profiles, while providing a relief valvesystem that beneficially provides release of the drug when thethrough-hole is partially or fully clogged. Thus, the device may operateto release drug via the preformed orifice unless and until thehydrostatic pressure within the drug reservoir reaches a thresholdpressure of the restraining plug(s), at which point release via therestraining plugs occurs. For example, release of the drug through theat least one preformed through-hole may be osmotically driven.

In a second aspect, as shown in FIGS. 5-6, the drug delivery devices 50described herein include sealed distal ends (shown sealed with adhesive70), with one or more restraining plugs 56 in contact with the elasticportion(s) 54 of the device body 52, to permit drug release viapreformed release port(s) 68 in the device body 52 (e.g., sidewall)adjacent the restraining plug 56. The elastic portions 54 may be at ornear the ends of the device 50 (as shown in FIGS. 9-10), or may beotherwise disposed along the length of the device, such as at or nearthe center of the device. The retraining plug(s) 56 may be situatedadjacent the one or more preformed release port(s) 68 in the device body52, such that the restraining plug(s) 56 cover, and effectively close,the preformed release port(s) 68 when the threshold hydrostatic pressurewithin the drug reservoir 60 has not been reached. In such embodiments,the restraining plugs 56 and elastic portions 54 of the device may besimilar to those described above and in U.S. Patent ApplicationPublication 2016/0008271 to Lee, except that the one or moremicrochannels 62 transiently formed upon the drug reservoir 60 reachinga threshold hydrostatic pressure extend from the drug reservoir 60 tothe preformed release port(s) 68.

Thus, in certain embodiments, as shown in FIGS. 5-6, a drug deliverydevice 50 includes a tubular body 52 that comprises a wall bounding areservoir 60 defined within the body, the wall having a water-permeableportion 64 and an elastic portion 54 having at least one preformedrelease port 68 (e.g., through-hole, aperture, orifice, slit) disposedtherein; a drug formulation 58 which contains a drug, the drugformulation 58 being disposed within the reservoir 60, wherein thewater-permeable portion 64 of the wall permits water to enter the drugdelivery device and contact the drug formulation 58 located in thereservoir 60; and at least one restraining plug 56 secured within thereservoir 60 in contact with the elastic portion 54 of the body 52 andadjacent the at least one preformed release port 68, such that the atleast one restraining plug 56 controls release of the drug from thedevice, via the at least one preformed release port 68, by the transientformation of one or more microchannels 62 between the elastic portion 54of the body and the at least one restraining plug 56, extending to theat least one preformed release port 68, upon the generation of ahydrostatic pressure within the reservoir 60 effective to form the oneor more microchannels 62. In certain of these embodiments, the at leastone preformed release port 68 is a through-hole or a slit disposed inthe wall of the body 52.

Any suitable number and location of restraining plugs 56 and preformedrelease ports 68 may be used, to achieve the desired drug releaseprofile. For example, as shown in FIG. 5B, the device 50 may include twopreformed ports 68, here shown as apertures, spaced 180 degrees from oneanother in a tubular device body 52, such that a single restraining plug56 is positioned adjacent both apertures. As shown in FIG. 5B, a pair ofapertures 68 and a corresponding restraining plug 56 may be provided ator near each distal end of the device. For example, as shown in FIG. 6B,a single preformed port 68, here shown as a slit, may be disposedadjacent each restraining plug 56. As shown in FIG. 6B, a preformed port68 and a corresponding restraining plug 56 may be provided at or neareach distal end of the device.

In some embodiments, the drug delivery device includes a permeationsystem as described in WO2014/145638 and U.S. Publication 2016/0310715,which are herein both incorporated by reference in its entirety. In someembodiments, the drug delivery device includes a housing having a closeddrug reservoir lumen bounded by a first wall structure and a hydrophilicsecond wall structure; and a drug formulation comprising trospiumcontained in the drug reservoir lumen, wherein the first wall structureis permeable or impermeable to water and impermeable to the drug, andthe second wall structure is permeable to trospium.

In some embodiments, the device housing has walls bounding and definingthe drug reservoir of the device that are made of a first material thatserves as the first wall structure and a second material that serves asthe second wall structure, such that drug release occurs essentiallyonly through the second material. In one embodiment, the device does notinclude an aperture; drug release is only by diffusion through thesecond wall structure. As used herein, the terms “impermeable to thedrug” and “impermeable to water” refer to the wall structure beingsubstantially impermeable to the drug or to water, such that essentiallyno drug or water is released via the wall structure over the therapeuticrelease period. For use in the bladder, it is desirable that the devicebe compliant (i.e., easily flexed, soft feeling) during detrusor musclecontraction in order to avoid or mitigate discomfort and irritation tothe patient. Thus, the durometer of the first and second materials ofconstruction are a design consideration, and the proportion of a highdurometer material may be limited in constructing a device housing of agiven size while keeping it suitably compliant in the bladder. Forexample, Tecophilic™ thermoplastic polyurethane (Lubrizol Corp.) mayhave a Shore hardness greater than 70 A, such as from 80 A to 65 D,while silicone tubing which may have a Shore hardness of from 50 A to 70A. Accordingly, it can be advantageous to utilize the combination ofthese two different polymeric materials, rather than making the deviceentirely of the water-swelling hydrophilic, drug-permeable secondmaterial.

The arrangement of the first and second wall structures can take avariety of forms. In certain embodiments, the first wall structure is acylindrical tube and the second wall structure is an end wall disposedat least one end of the cylindrical tube, or the first wall structureand the second wall structure are adjacent one another and together forma cylindrical tube. That is, drug release is controlled by drugdiffusion through a drug-permeable component defining a portion of theclosed device housing. The drug-permeable wall structure may be located,dimensioned, and have material properties to provide the desired rate ofcontrolled drug diffusion from the device. In some embodiments, the drugpermeable wall may include a disk stabilized in the lumen of a tube ator near an end of the tube, optionally sandwiched between an innerwasher and an outer washer. In some embodiments, the drug permeable wallis part of a sidewall of a tubular housing, or part of an end pluglocated at the end of a tubular housing.

The length and width of the wall portion formed of the water permeablematerial may be selected to provide a desired rate of water flux intothe reservoir defined by device housing. In one embodiment, the width ofthe water permeable wall portion may be quantified by the arc angledefining the wall when viewed in cross-section normal to the luminalaxis. The water permeable region(s) of the device housing can becontrolled to give a selected area of, and thus rate for, osmotic waterimbibition, and yet advantageously maintain suitable overall dimensionsand elasticity of the device, formed of suitable biocompatibleelastomers. Advantageously by forming the device housing by aco-extrusion process, the structural variations of the water permeableregion(s) can be created with conventional co-extrusion equipment byselection of the processing parameters, thereby beneficially providingthe ability to cost-effectively manufacture multiple structural deviceconfigurations. In some embodiments, the length of the water permeableregions(s) runs along only a portion of the overall length of thedevice. In such an embodiment, larger arc angles of the water permeableregion(s) can therefore be employed while keeping the rate of drugrelease at a desirable level over an extend period of time. Suchintravesical device housings are described, for example, in US2016/0310715.

In some embodiments, the wall may have a varied thickness over thecircumference of the wall, for example the drug permeable portion mayhave a thickness that is less than the thickness of the drug impermeableportion. Moreover, the thinner drug permeable wall structure may bedisposed at various positions relative the adjacent, thicker drugimpermeable wall structure. In some embodiments, drug release iscontrolled by drug diffusion through a drug-permeable component defininga portion of the closed device housing. The drug-permeable wallstructure may be located, dimensioned, and have material properties toprovide the desired rate of controlled drug diffusion from the device.

In some embodiments, the drug delivery device comprises a housingcomprising a first wall structure and a second wall structure that areadjacent one another and together form a tube defining a drug reservoirlumen; and a drug contained in the drug reservoir lumen, wherein: (i)the second wall structure, or both the first wall structure and thesecond wall structure, are permeable to water, (ii) the first wallstructure is impermeable to the drug and the second wall structure ispermeable to the drug, such that the drug is releasable in vivo bydiffusion through the second wall structure, (iii) the second wallstructure comprises less than 90 percent of a cross sectional area ofthe tube, in a cross section normal to the longitudinal axis of thetube, (iv) and the first wall structure comprises a first polyurethanecomposition.

In some embodiments, the device comprises an elongated, elastic housinghaving a drug reservoir lumen extending between a first closed end and asecond closed end; and a drug contained in the drug reservoir lumen,wherein (i) the housing comprises a tubular wall structure whichcomprises: a first annular segment formed entirely of a first materialwhich is impermeable to the drug, and a second annular segment formed atleast partially of a second material which is permeable to the drug andconfigured to release the drug in vivo by diffusion through the secondmaterial in the second annular segment, and (ii) the first annularsegment has a first end which is integrally formed and connected with afirst end of the second annular segment.

In some embodiments, the walls that define the drug reservoir lumens mayhave varying thickness. Housings with walls of different thicknesses mayimprove the housing's flexibility, compressibility, or both. Differentwall thicknesses also may aid in securing a solid drug unit in the drugreservoir lumens.

In some embodiments, the intravesical device body, or housing, mayinclude openings (e.g., at the opposed ends of an annular tube) in needof sealing following loading of the drug reservoir with the drugpayload, during the assembly process. Any of these defined openings orends of the housings, including the monolithic housing and modularhousing units, may be sealed, if desired to close off an opening. Thissealing may be accomplished with a sealing substance or structure. Thesealing structure may be formed of biocompatible material, including ametal such as stainless steel, a polymer such as silicone, a ceramic, orsapphire, or adhesive, among others or combinations thereof. The sealingsubstance or structure may be biodegradable or bioerodible. In oneembodiment, a medical grade silicone adhesive or other adhesive isloaded into the opening in a fluid or workable form and then cure withinthe housing opening to seal it. In some embodiments, the housingincludes one or more predefined apertures for release of the drug fromthe device. These drug-release apertures are not the defined openingswhich are sealed. In other embodiments, the housing does not include apredefined drug-release aperture.

In some embodiments the device releases drug without a predefined drugrelease aperture (i.e., orifice). Release of drug from a device withouta predefined drug-release aperture may be driven by diffusion or osmoticpressure. Examples of such suitable “no-orifice” release systems aredescribed in PCT Patent Application Publication No. WO 2014/144066 (TB130) and U.S. Patent Application Publication No. 2014/0276636 (TB 134),which are incorporated herein by reference.

In some embodiments, the drug delivery device includes an osmotic systemas described in U.S. Publication 2016/0199544, U.S. Pat. No. 8,679,094,and U.S. Publication 2016/0008271, which are herein incorporated byreference.

In some embodiments, the drug delivery device includes an osmotic systemas described in U.S. Publication 2016/0279399 (TB 137), which is hereinincorporated by reference. In some embodiments using such systems,trospium may be loaded into the device housing in a liquid form prior toinsertion of the device into the bladder of the individual.

In some embodiments, the device comprises a housing defining areservoir; a first unit contained within the reservoir, the first unitcomprising a drug; and a second unit contained within the reservoir in aposition distinct from the first unit, wherein the second unit comprisesa functional agent that facilitates in vivo release of trospium fromhousing. In some embodiments, the device comprises a housing defining areservoir; a first unit contained within the reservoir, the first unitcomprising a drug; and a second unit contained within the reservoir in aposition distinct from the first unit, wherein the second unit comprisesa functional agent that facilitates stabilization of trospium in urinein the bladder (i.e., anti-protease agent). In some embodiments, thefirst unit comprises one or more solid tablets or powders which compriseat least one drug (e.g., trospium, such as gemcitabine), and the secondunit comprises one or more solid tablets or powders (e.g., whichcomprise an osmotic agent, such as urea). In some embodiments, thehousing is in the form of an elongated elastomeric tube having a lumen(i.e., the reservoir) in which all of the solid tablets of the first andsecond units are aligned and contained. The diameter of the solidtablets may be substantially the same as the diameter of the lumen.

When osmotic release is the desired drug release mode, the functionalagent in the second units may include an osmotic agent that facilitatesosmotic release of the drug. For example, the osmotic agent may have ahigher solubility than the drug, such that the osmotic agent expeditessolubilization and/or subsequent release of the drug. This beneficiallyallows for the delivery of low solubility or other drugs typically onlydelivered via diffusion, from osmotic delivery-based devices. The devicemay exhibit an induction period while a sufficient volume of functionalagent and/or drug are solubilized to achieve the osmotic pressuregradient.

Subsequently, the device may exhibit a zero-order release rate for anextended period, followed by a reduced, non-zero-order release rate overa decay period. A desired delivery rate can be achieved bycontrolling/selecting various parameters of the device, including butnot limited to the surface area and thickness of the water permeablewall; the permeability to water of the material used to form the wall;the shape, size, number and placement of the apertures; and thedissolution profiles of the drug and functional agent.

The devices described herein may also be configured to release drug viadiffusion, alone or in combination with osmotic release. The device maybe configured to allow the solubilized drug to pass through a portion ofthe housing or one or more apertures therein.

Alternatively, or in combination with a water permeable wall portion,the housing may include at least one aperture configured to permit afluid to enter the reservoir in vivo. The housing may also include oneor more apertures or passing pores configured to permit solubilized drugto pass there through.

In some embodiments of the osmotic system, the device housing includes afirst elastomeric material that is water permeable and a secondelastomeric material that is water impermeable, wherein both materialsare selected to be impermeable to the drug contained in the housing.

FIGS. 7A-7C illustrate one embodiment of an intravesical device usefulin the methods described herein. The device 100 includes a drugreservoir portion 102 and a retention frame portion 104. In FIG. 7A, thedevice 100 is shown in a relatively expanded shape suited for retentionwithin the urinary bladder of an individual. In FIG. 7C, the device 100is shown in a relatively lower-profile shape for deployment through theworking channel 202 of a deployment instrument 200, such as a cystoscopeor other catheter, e.g., for insertion into and through the urethra andinto the bladder of the patient. Following deployment (release of thedevice) into the bladder, the device 100 may assume the relativelyexpanded shape to retain the drug delivery device in the bladder. In theillustrated embodiment, the drug reservoir and retention frame portions102, 104 of the drug delivery device 100 are longitudinally aligned andare integrally formed or otherwise coupled to each other along theirlength.

The drug delivery device 100 includes an elastic or flexible device body106 that defines a drug reservoir lumen 108 and a retention frame lumen110. The drug reservoir lumen 108 is configured to house a drug (e.g.,trospium) which is in the form of a plurality of solid drug units 112,to form the drug reservoir portion 102. Interstices 116 or breaks formedbetween adjacent drug units 112 permit the drug units 112 to move withreference to each other so that the device 100 is flexible despite beingloaded with drug in solid form. The retention frame lumen 110 isconfigured to house a retention frame 114 to form the retention frameportion 104.

As shown in the cross-sectional view of FIG. 7B, the device body 106includes a tube or wall 122 that defines the drug reservoir lumen 108and a tube or wall 124 that defines the retention frame lumen 110. Thetubes 122, 124 and lumens 108, 110 can be substantially cylindrical,with the drug reservoir lumen 108 having a relatively larger diameterthan the retention frame lumen 110, although other configurations can beselected based on, for example, the amount of drug to be delivered, thediameter of the retention frame, and deployment considerations such asthe inner diameter of the deployment instrument. The device body 106 maybe formed integrally, such as via molding or extrusion, althoughseparate construction and assembly of the tubes 122, 124 is possible.The wall 124 that defines the retention frame lumen 110 may extend alongthe entire length of the wall 122 that defines the drug reservoir lumen108, so that the retention frame lumen 110 has the same length as thedrug reservoir lumen 108 as shown, although one wall may be shorter thanthe other wall in other embodiments. Further, the two walls 122, 124 areattached along the entire length of the device in the illustratedembodiment, although intermittent attachment can be employed.

As shown in FIG. 7A, the drug reservoir lumen 108 is loaded with anumber of drug units 112 in a serial arrangement. For example, betweenabout 10 and about 100 drug units 112 may be loaded, such as betweenabout 20 and about 80 drug units 112. The drug units may, for example,be tablets, beads, or capsules. Essentially any number of drug units maybe used, depending upon the sizes of the reservoir and the drug units.The drug reservoir lumen 108 includes open ends 130 and 132, which areshown as relatively circular openings at opposite ends of the drugreservoir lumen 108. At least one of the openings provides ingress forthe drug units 112 to be placed into the drug reservoir lumen 108 duringdevice loading and assembly.

End plugs 120 block openings 130 and 132 following loading of the drugunits 112. The end plugs 120 may be cylindrical and may be secured inthe drug reservoir lumen 108 by frictional engagement and/or an adhesiveor other fastening means. Each end plug 120 includes an aperture 118, asillustrated, to provide a passageway for releasing drug from the drugreservoir lumen 108. In some alternative embodiments, only one of theend plugs includes an aperture. In some other alternative embodiments,neither of the end plugs includes an aperture, and in some of thoseembodiments, the tube wall 122 includes a defined aperture for releaseof drug therethrough.

The retention frame lumen 110 is loaded with the retention frame 114,which may be an elastic wire, such as a nitinol wire, (thermally)shape-set into the overlapping coiled shape shown in FIG. 7A. Theretention frame 114 may have an elastic limit and modulus that allowsthe device 100 to be introduced into the body in a relativelylower-profile shape, permits the device 100 to return the relativelyexpanded shape once inside the body, and impedes the device fromassuming the relatively lower-profile shape within the body in responseto expected forces, such as the hydrodynamic forces associated withcontraction of the detrusor muscle and urination.

e. Erosion-Based Systems

In some embodiments, which may be used with tablets comprisinglow-solubility drugs, the drug is provided in tablet form secured in thedevice with exposed tablet faces, such that release of drug from thedevice occurs by controlled erosion/dissolution, as described in U.S.Pat. No. 9,107,816. In some embodiments, the device may comprise modularhousings. The modular housings are typically formed from at least twoseparate housing units, each unit housing at least one solid drug unit.The material from which each housing unit is formed defines at least onedrug reservoir lumen capable of housing a solid drug unit. The drugreservoir lumens may have one or more defined openings. For example, thedrug reservoir lumen may have two opposed openings which exposecorrespondingly opposed end surfaces of the at least one solid drug unithoused therein. In certain embodiments, the at least two separatehousing units in the modular housings are connected, directly orindirectly, by a retention frame. In some embodiments, the modularhousing units may be placed on the retention frame to form a “bracelet”design. The devices may have one housing unit or a plurality of housingunits. The number of housing units may be limited only by the size ofthe retention frame by which they are connected.

In some embodiments, one or more of the separate housing units includesa retention frame lumen through which a shared retention frame isextended. In certain embodiments, the retention frame lumen and the drugreservoir lumen of each housing unit are arranged parallel to eachother. In particular embodiments, the retention frame lumen and the drugreservoir lumen of each housing unit are arranged perpendicular to eachother. In further embodiments, the retention frame lumen and the drugreservoir lumen of each housing unit are arranged at an angle other than0° (parallel) and 90° (perpendicular), such as 5, 10, 30, 45, 60, or85°. In further embodiments, the devices described herein include two ormore housing units with at least two of the following configurations:(1) the retention frame lumen and drug reservoir lumen are arrangedsubstantially parallel to each other, (2) the retention frame lumen anddrug reservoir lumen are arranged substantially perpendicular to eachother, and (3) the retention frame lumen and drug reservoir lumen arearranged at an angle other than 0° (parallel) and 90° (perpendicular).

f. Integrated Silicone-Drug Delivery Systems

In some embodiments, the device may comprise an elastic polymer-drugmatrix as described in WO2015/200752, which is herein incorporated byreference in its entirety.

g. Devices with Multiple Release Portions

In some embodiments, the device includes at least two drug releaseportions, at least one release portion releasing drug at a differentrate than another release portion as described in WO2011/031855 which isherein incorporated by reference in its entirety. The release portionsmay achieve different release rates by having different configurations,by housing different drug formulations, or by employing differentrelease mechanisms, among others or combinations thereof. The releaseportions may be combined to achieve a desired release profile. Forexample, the device may include release portions that exhibit differentinduction or lag times before the onset of initial release, that releasedrug at different rates or according to different release curves afterthe onset of release, or that release drug for different periods beforethe drug load is substantially exhausted, among others or combinationsthereof. The disparate release portions may be combined to achieve adesired release profile from the drug delivery device as a whole, suchas a release profile that demonstrates a relatively short initial lagtime and thereafter demonstrates continued release at a relativelyconstant rate over an extended period.

In some embodiments, the devices are loaded with drugs in the form of anumber of solid drug tablets, which may be smaller in size thanconventional drug tablets. Because the devices control release of thedrug into the body, the drug itself may include little or no excipientsthat control drug release. Instead, the excipients present in the drugtablets may be present primarily or completely to facilitate thetableting process or solubilization in vivo. Thus, the devices mayprovide a high drug payload on a volume or weight basis, yet the devicesmay be small enough for in vivo deployment in a minimally invasivemanner.

The drug housing also permits the egress of drug, in either liquid orsemi-solid form as implanted or following in vivo solubilization. Thewall may be formed from a drug-permeable material that permits drugefflux through the drug housing along its entire length. The wall alsomay be formed from a material that is semi-permeable to the drugdepending at least in part on the drug form. For example, the wall maybe permeable to the drug in one form, such as a charged form, but notanother form, such as uncharged form (e.g., base form versus salt form).The wall also may include one or more openings or passageways formedcompletely through it that permit drug to exit the drug housing.

The drug portion can have any combination of the characteristics orconfigurations described herein, meaning the aperture may be provided,omitted, substituted with a passing pore, or augmented with additionalapertures or passing pores; the housing may have a porous wall with anopen-cell structure or a closed-cell structure; one or more degradabletiming structures or release modulating structures may be associatedwith the housing, or any combination thereof.

The drug tablets may be aligned in any arrangement other than a serialarrangement, depending on the configuration of the drug housing. Thedrug tablets may fill any portion of the drug housing other than theentire drug housing as illustrated. A filling material such as siliconeadhesive can be used to fill any portion of the drug housing that is notloaded with drug tablets, or air may be used, increasing the buoyancy ofthe device. The composition of the drug tablets may be the same or mayvary along the device. The drug also may be in forms other than a drugtablet, such as other liquid, semi-solid, or solid forms (e.g.,granules).

In some embodiments, the drug delivery device includes at least twodiscrete or segregated drug portions associated with a single retentionportion. The drug portions may be separate drug housings each associatedwith the retention portion, or the drug portions may be separate areaswithin a single drug housing that is associated with the retentionportion.

Each drug portion may be defined by a portion of the wall of the drughousing and at least one partition structure, which separates the drugportion from a second drug portion. The partition structure may be aplug inserted into the housing, such as a cylinder, sphere, or disk,among others, which is secured in place due to its size or with anadhesive. The partition structure also may be a portion of the housingformed directly therein, such as by molding.

A device with at least two discrete portions may be suited forcontrolled release of at least two drug payloads from a correspondingnumber of drug reservoirs. The two discrete portions may have the sameconfigurations or different configurations as described herein. The twodrug payloads may be the same as each other or may differ from eachother with reference to content, such as active ingredient content orexcipient content; form, such as salt form or base form; state, such asliquid, semi-solid, or solid state; among others or combinationsthereof. Thus, the two discrete portions may release the two drugpayloads at the same time or at different times, at the same rate or atdifferent rates, via the same release mechanisms or different releasemechanisms, or any combination thereof.

For example, one drug portion may be configured to release its drugpayload relatively quickly after implantation and another drug portionmay be configured to experience an induction time before beginningrelease, or a combination thereof. The onset of release of two payloadsin different drug portions can be staged. Examples of quick release drugportions include a drug portion that operates as a relativelyfast-acting osmotic pump, such as a silicone tube having a relativelythinner wall, a drug portion that is loaded with drug in a quick releaseform, such as liquid form or a specially formulated solid form, a drugportion associated with a relatively fast-acting degradable timingstructure, or combinations thereof. Thus, the device may release drugduring an initial, acute phase and during a maintenance phase.

As another example, one drug portion may be configured to release itsdrug payload at a relatively faster rate than the other drug payload.For example, one drug portion may house a drug payload with low watersolubility for diffusive release that is initiated relatively soon afterimplantation, and another drug portion may house a drug payload that ishighly water soluble for osmotic release after an induction period. Asanother example, one drug portion may house a drug payload in a liquidstate for quick release through an aperture having a fast-actingdegradable timing membrane, and another drug portion may house anotherdrug payload of solid tablets for slow release following solubilizationin vivo. As still another example, one drug portion may have arelatively solid wall while another drug portion may have a number ofapertures or pores formed through its wall, which may increase therelease rate due to diffusion, or a closed-cell porous wall, which mayincrease the release rate due to increased permeation of water or drugthrough the wall.

The release portions may be combined to achieve a desired releaseprofile. For example, the device may include release portions thatexhibit different induction or lag times before the onset of initialrelease, that release drug at different rates or according to differentrelease curves after the onset of release, or that release drug fordifferent periods before the drug load is substantially exhausted, amongothers or combinations thereof. The disparate release portions may becombined to achieve a desired release profile from the drug deliverydevice as a whole, such as a release profile that demonstrates arelatively short initial lag time and thereafter demonstrates continuedrelease at a relatively constant rate over an extended period.

By combining multiple distinct drug portions in a single device, thedevice may exhibit a desired release profile of trospium. The releaseprofile from the device as a whole may be the sum of the releaseprofiles of the discrete portions, for example, with the first portionexhibiting minimal lag time before the onset of release, the secondportion exhibiting a short induction period as the osmotic pressuregradient develops, and the third portion exhibiting a longer delaybefore onset as the degradable structure dissolves or degrades. Oncerelease begins from any one portion, the release rate may be relativelyzero-order for an extended period, followed by a period of decay. Itshould be noted that the three discrete portions are examples, and thatany number or combination of discrete portions may be used to achievethe desired release profile.

Because the different drug portions may be merely segregated areaswithin in a single tubular housing, the device advantageously may berelatively simple to construct and deploy, and yet the different drugportions exhibit different release profiles due to the different drugpayloads, aperture placement, and degradable timing structures. In otherembodiments in which the drug portions use, for example, walls ofdifferent materials, thicknesses, or porous cell structures, the housingmay vary along its length or separate drug housings may be used. Thus,controlled release may be achieved in a range of manners.

II. Gels

In another embodiment, a coating substance may be intravesically appliedto the bladder wall (e.g., to an area of the urothelium inside theurinary bladder), wherein the coating substance includes trospium andone or more excipient materials that promote adherence of the coatingsubstance to the bladder wall and provides continuous controlled releaseof trospium over the treatment period. The coating substance may be amucoadhesive formulation, such as gels, ointments, creams, pastes,films, emulsion gels, tablets, polymers, or a combination thereof.Mucoadhesive formulation polymers may include hydrogels or hydrophilicpolymers, polycarbophil (e.g., Carbopols, etc.), chitosan,polyvinylpyrrolidone (PVP), lectin, polyethyleneglycolated polymers,celluloses, or a combination thereof. Suitable celluloses include methylcellulose (MC), carboxymethyl cellulose (CMC), hydroxypropyl cellulose(HPC), or combinations thereof. The coating substance may include apermeation enhancer. Non-limiting examples of permeation enhancersinclude dimethyl sulfoxide (DMSO), sodium carboxymethyl cellulose(NaCMC), lipids, surfactants, or combinations thereof. A coatingsubstance may be deployed in the bladder so that the coating substanceengages the bladder wall.

The coating substance may be deployed in the bladder using a deploymentinstrument. The deployment instrument may be any device designed tonavigate natural lumens of the body to reach the intended implantationsite. For deployment in the bladder, the deployment instrument may besized and shaped for passing through the individual's urethra orsuprapubic cystostomy or suprapubic catheter to the individual'sbladder. The deployment instrument may be a known device, such as acatheter or cystoscope, or a specially designed device. The deploymentinstrument is used to deploy the coating substance into the body and issubsequently removed from the body, leaving the coating substance whollyimplanted in the body. Once so implanted, the coating substance mayrelease drug into the body for an extended period. A comparableprocedure can be used to deploy any of the devices or drugs describedherein into other parts of the body through other natural lumens. Forexample, a deployment instrument can be used to deploy a liquid drug ordrug formulation into the bladder by passing the deployment instrumentthrough a urethra or suprapubic cystostomy.

EXAMPLES Example 1 Intravesical Delivery of Trospium for Treatment ofOveractive Bladder

The purpose of this study was to confirm a sustained local delivery oftrospium with Trospium-Releasing Intravesical System (TAR-302). TAR-302is a passive, nonresorbable trospium-releasing intravesical system whoseprimary mode of action is the controlled release of trospium into thebladder over a period of time, for example, a 42-day period.

I. Part A.

Ten subjects were included in this study. These subjects were idiopathicoveractive bladder patients who have failed oral medications. TAR-302was placed into the bladder through an inserter on Study Day 0 and wasremoved on Study Day 42. TAR-302 releases trospium gradually during the42 day indwelling time in a dose of about 4 to 8 mg per day in thebladder. See FIG. 3A.

Daily urinary recovery of trospium was assessed on Day 3, 7, 21, 35, 42and 56. Average total daily recovery of trospium on PK sampling days isabout 6.28 mg/day, ranging from 3.03 to 8.31 mg/day. The gray dash linerepresents the estimated daily recovery of trospium with an oraltrospium administration at a dose of about 20 mg BID or 60 mg QD1. SeeFIG. 8.

The TAR-302 therapy resulted in a benign adverse event profile. Noevidence of classical antimuscarinic systemic side effects, retention,or encrustation was observed. At the end of dosing (i.e., Day 42),average daily incontinence episodes reduced from the baseline of 5.42 to1.28. See FIG. 9B. The efficacy of TAR-302 in oral refractory patientsis superior to Botox®, which resulted in a reduction of 2.7 in averagedaily incontinence episodes from baseline. See FIG. 10A. The efficacy ofTAR-302 is also superior to oral treatments of VESIcare® (solifenacinsuccinate) and Detrol® LA (tolterodine tartrate), which respectivelyresulted in a reduction of 1.4 and 0.8 in average daily incontinenceepisodes from baseline. See FIG. 10B. More strikingly, a durableresponse was observed after the removal of TAR-302. At Day 84, six weeksafter the removal of TAR-302, subjects averagely had 2.44 dailyincontinence episodes, which is 55% less than the baseline of 5.42episodes. See FIG. 9B.

Urinary bother scores and quality of life scores were also significantlyimproved by TAR-302 as shown in FIGS. 11-12. After 42 days of treatmentwith TAR-302, a 40.3% decrease in bother score was observed. Six weeksafter removal of TAR-302, the bother score was reduced by 19.1 points, aclinically meaningful improvement. FIG. 12. Similarly, at the end of the42 day treatment period with TAR-302 a significant 42.2 point increasein quality of life score was observed. Even six weeks after removal ofTAR-302, at day 84, a significant 17.9 point improvement of quality oflife score was observed.

a. Outcome measures

Primary Outcome Measures include safety of TAR-302 was assessedthroughout the study based on reported adverse event (AE),investigational product events (IPEs), physical examinations (PEs),vital signs, clinical laboratory tests, scheduled cystoscopicexaminations, bladder ultrasounds, bladder post-void residual volume(PVR), and the use of concomitant medications.

Secondary outcome measures include the following.

1. Tolerability of TAR-302 was assessed throughout the study based upon,for example, percent of subjects who were tolerant of TAR-302 indwellingfor the designated period of time and did not require TAR-302 removalprior to the scheduled date of removal due to meeting any of the SubjectStopping Criteria or other drug or device constituent related adverseevent.

2. Pharmacokinetic Analysis of Plasma and Urine was assessed from Day 0to Day 56. For example, plasma trospium exposure and urinary trospiumexposure were tested and analyzed.

3. Reduction in incontinence over baseline was assessed from Day 0 toDay 84. For example, a negative change from baseline in number of dailyepisodes of urinary incontinence, where incontinence is defined as anincident of involuntary loss of urine, was assessed and analyzed.

4. Reduction in daily micturition episodes was assessed from Day 0 toDay 56. For example, a negative change from baseline in the number oftimes a subject urinates into the toilet was assessed and analyzed.

5. Increase in voided volume per micturition was assessed from Day 0 toDay 56. For example, an increase over baseline as measured over separate24-hour periods was assessed and analyzed.

Other Outcome Measures include Quality of Life (QoL) which was assessedfrom Day 0 to Day 84. For example, evidence of improvement in QoL wereassessed by having the subject answering any or a combination of thefollowing questions that during the past four weeks: a. the extent towhich the subject was bothered by an uncomfortable urge to urinate; b.the extent to which the subject was bothered by a sudden urge to urinatewith little or no warning; c. the extent to which the subject wasbothered by accidental loss of small amounts of urine; e. the extent towhich the subject was bothered by nighttime urination; f. the extent towhich the subject was bothered by waking up at night because he/she hadto urinate; g. the extent to which the subject was bothered by urineloss associated with a strong desire to urinate; h. how often have thesubject's bladder symptoms caused the subject to plan “escape routes” torestrooms in public places; i. how often have the subject's bladdersymptoms made the subject feel like there is something wrong withhim/her; j. how often have the subject's bladder symptoms interferedwith his/her ability to get a good night's rest; k. how often have thesubject's bladder symptoms made him/her frustrated or annoyed about theamount of time he/she spent in the restroom; 1. how often have thesubject's bladder symptoms made him/her avoid activities away fromrestrooms (e.g., walking, running, hiking); m. how often have thesubject's bladder symptoms awakened the subject during sleep; n. howoften have the subject's bladder symptoms caused the subject to decreasehis or her physical activities (exercising, sports, etc.); o. how oftenhave the subject's bladder symptoms caused the subject to have problemswith his/her partner or spouse; p. how often have the subject's bladdersymptoms made the subject uncomfortable while traveling with othersbecause of needing to stop for a restroom; q. how often have thesubject's bladder symptoms affected his/her relationships with familyand friends; r. how often have the subject's bladder symptoms causedhim/her embarrassment; s. how often have the subject's bladder symptomscaused him/her to locate the closet restroom as soon as he/she arrive ata place he/she have never been.

b. Eligibility Criteria

Inclusion criteria include the following. 1. The subject has symptoms ofoveractive bladder (OAB) (frequency/urgency) with urge urinaryincontinence or mixed urinary incontinence with a predominant urgecomponent for at least 6 months. For example, the subject has eight ormore voids per 24 hours as recorded in a diary, or at least 4incontinence episodes associated with urgency recorded in a 3-day diary(the subject must have at least one episode that occurs each 24 hours orper day). 2. The subject has inadequate response or limiting sideeffects with anticholinergics for the treatment of OAB.

Exclusion criteria include the following. 1. Age of the subject is lessthan 18 years. 2. OAB is caused by a neurological condition. 3. There issignificant renal dysfunction at screening (Glomerular Filtration Rate<30 mL/min). 4. There is significant polyuria of any cause at screening(urine output >4,000 mL/day). 5. There is a history of pelvic radiation.6. There is a history of either bladder cancer or bladder pathology thatthe investigator deems unfit for study inclusion. 7. There is an activemalignancy within 12 months with the exception of those with anegligible risk of metastasis or death treated with expected curativeoutcome. 8. The subject has any bladder or urethral anatomic featurethat may prevent the safe placement, indwelling use, or removal ofTAR-302. 9. In the opinion of the investigator, the subject has ahistory of significant stress urinary incontinence. 10. The subject hasan active bladder stones or history of bladder stones <6 months prior tostudy entry. 11. The subject has a history of recurrent symptomaticurinary tract infections (UTIs) (>4 per 1 year). 12. The subject haseither urinary retention or gastric retention or uncontrollednarrow-angle glaucoma. 13. The subject has a post-void residual volume(PVR) of 300 mL or greater. 14. The subject has a known hypersensitivityto trospium, chemically-related drugs, or component excipients. 15. Thesubject has a known hypersensitivity to the device materials, includingsilicone and nitinol. 16. The subject actively takes oral trospium. 17.The addition of a new or a change in dose to a current medication forthe treatment of OAB (i.e. anticholinergics, beta-3 adrenergic agonists,antispasmodics, antidepressants, or hormones) within 30 days prior tosigning the informed consent form (ICF). A stable dose must continuethrough the final study visit. If previously used and discontinued,these medications must have been stopped for >2 weeks prior to Day 0.18. There is an intravesical onabotulinum toxin use within the last 9months prior to the Screening Visit. 19. Intravesical anticholinergicmedications were used within the last 30 days prior to the ScreeningVisit. 20. The subject has a history of non-medication based therapy(i.e. InterStim therapy) for the treatment of OAB. History ofnon-invasive neuromodulation (i.e. Percutaneous Tibial Nerve Stimulation(PTNS)) is allowed if discontinued at least 8 weeks prior to Study Day0. 21. Female subject who is pregnant (as verified by urine test at timeof screening) or lactating or of childbearing potential and not usingacceptable methods of contraception. 22. The subject has a medicalcondition that may cause noncompliance with the study protocol. 23. Thesubject has participated in another drug, device, or behavioral studywithin 60 days prior to the Screening Visit. 24. The subject has ahistory or presence of any significant cardiovascular, pulmonary,hepatic, renal, gastrointestinal, gynecological, endocrine,immunological, dermatological, neurological or psychiatric disease ordisorder that, in the opinion of the investigator, contraindicatesparticipation. 25. History of any of the following within 3 months priorto Screening Visit. Major illness/major surgery (requiringhospitalization), including pelvic, lower back surgery or procedureunrelated to bladder cancer; most outpatient procedures are notexclusionary; renal or ureteral stone disease or instrumentation;Childbirth.

II. Part B.

This open label Phase 1 b study evaluated the safety, tolerability, andpreliminary efficacy of TAR-302 in patients with idiopathic overactivebladder (iOAB) refractory or intolerant to oral therapy. Study subjectswere required to have at least 4 incontinence episodes over 3 days atstudy entry. Subjects received a single administration of TAR-302 for 42days of intravesical dwell time. TAR-302 was placed with an insertioncatheter and removed via cystoscope. Pharmacokinetic (PK) analyses wereconducted in blood and urine. Response to TAR-302 was assessed using3-day voiding incontinence diaries and quality of life was assessedusing the OAB-q Short Form (OAB-q SF).

Results

Eleven subjects successfully completed the study. Baselinecharacteristics are presented in Table 1. TAR-302 was well toleratedthroughout the study: AEs potentially related to TAR-302 were all mild,and included hematuria (n=4), bladder discomfort (n=2), and bladder pain(n=2). There was only 1 AE observed typical of antimuscarinic exposure:a single report of transient dry mouth on day 36, which resolvedspontaneously. 2 subjects experienced UTIs, which were consideredpotentially related to insertion procedures.

PK analyses demonstrated urine that trospium levels averaged 3.27 μg/mLacross the study, well above predicted urine levels achieved with oraltrospium (0.5-1 μg/mL) (See Sanctura FDA Package Insert, accessed March2019). These intravesical concentrations produced negligible systemicexposure (average: 0.22 ng/mL).

TABLE 1 Demographics Demographic Total Age (median) 60 (range: 54-66)Female 11 (100%) Race Caucasian 9 (81.8%) Black/African American 2(18.2%) BMI (median) 29.3 (23.0-43.7)

Subjects experienced a reduction in mean daily urge incontinence (UI)episodes of 75%, from 5.57 events per day at baseline to 1.4 events atDay 42 (p<0.01). 3 of the 11 subjects were fully continent at Day 42.Subjects also experienced clinically and statistically significantimprovements in both symptom bother and health-related quality of life,as measured by the OAB-q SF: mean scores on the symptom bother subscaledecreased by 41 points (74 at baseline, 33 at day 42, p<0.01), and meanscores on the HRQOL subscale increased by 45 points (32 at baseline, 77at day 42, p<0.001).

Surprisingly, subjects appeared to experience durable symptom benefitwell after removal of TAR-302 at Day 42, despite no further therapeuticintervention during this period. Mean UI episodes remained significantlylower than baseline at Day 84 2.67 UI episodes/day, −52%, p<0.05);additional measures of UI improvement are noted in Table 2. Further,clinical (though not statistical) improvements on both OABq-SF subscaleswere also observed at Day 84: symptom bother decreased by 19 points (74at baseline vs. 55 at Day 84), and HRQOL increased by 18 points (32 atbaseline vs. 50 at Day 84; minimum clinically meaningful change=10points).

TABLE 2 UI Responder Analysis Assessment Day Statistic Total (N = 11)Pre-TAR-302 Removal (Day 42) >50% decrease from baseline n (%) 9/11(81.8) >70% decrease from baseline n (%) 7/11 (63.6) 100% decrease frombaseline n (%) 3/11 (27.3) Final Study Day (Day 84 +/− 7 days) >50%decrease from baseline n (%) 5 (45.5) >70% decrease from baseline n (%)2 (18.2) 100% decrease from baseline n (%) 0 (0.0)

TAR-302 has demonstrated encouraging safety, tolerability, andpreliminary efficacy in the management of symptoms for patients withurge urinary incontinence insufficiently controlled with oral therapies.

Example 2

In this study, TAR-302 is placed into the bladder of subjects withoveractive bladder through an inserter on Study Day 0 and is removed onStudy Day 56 immediately followed by another inserter of TAR-302, whichis removed on Day 112. The subjects are further treated with TAR-302 ona prn (as need) basis.

I. Outcome Measures

Primary Outcome Measures include safety of TAR-302 assessed throughoutthe study based on reported adverse event (AE), investigational productevents (IPEs), physical examinations (PEs), vital signs, clinicallaboratory tests, scheduled cystoscopic examinations, bladderultrasounds, bladder post-void residual volume (PVR), and the use ofconcomitant medications.

Secondary outcome measures include the following.

1. Tolerability of TAR-302 was assessed throughout the study based upon,for example, percent of subjects who were tolerant of TAR-302 indwellingfor the designated period of time and did not require TAR-302 removalprior to the scheduled date of removal due to meeting any of the SubjectStopping Criteria or other drug or device constituent related adverseevent.

2. Pharmacokinetic Analysis of Plasma and Urine assessed from Day 0 toDay 112. For example, plasma trospium exposure and urinary trospiumexposure are tested and analyzed.

3. Reduction in incontinence over baseline assessed for the duration ofparticipation in the study. For example, a negative change from baselinein number of daily episodes of urinary incontinence, where incontinenceis defined as an incident of involuntary loss of urine, are assessed andanalyzed.

4. Reduction in daily micturition episodes is assessed from Day 0 to Day112. For example, a negative change from baseline in the number of timesa subject urinates into the toilet is assessed and analyzed.

5. Increase in voided volume per micturition was assessed from Day 0 toDay 112. For example, an increase over baseline as measured overseparate 24-hour periods is assessed and analyzed.

Other Outcome Measures include Quality of Life (QoL) which is assessedfrom Day 0 to Day 112. For example, evidence of improvement in QoL isassessed by having the subject answering any or a combination of thefollowing questions that during the past four weeks: a. the extent towhich the subject was bothered by an uncomfortable urge to urinate; b.the extent to which the subject was bothered by a sudden urge to urinatewith little or no warning; c. the extent to which the subject wasbothered by accidental loss of small amounts of urine; e. the extent towhich the subject was bothered by nighttime urination; f. the extent towhich the subject was bothered by waking up at night because he/she hadto urinate; g. the extent to which the subject was bothered by urineloss associated with a strong desire to urinate; h. how often have thesubject's bladder symptoms caused the subject to plan “escape routes” torestrooms in public places; i. how often have the subject's bladdersymptoms made the subject feel like there is something wrong withhim/her; j. how often have the subject's bladder symptoms interferedwith his/her ability to get a good night's rest; k. how often have thesubject's bladder symptoms made him/her frustrated or annoyed about theamount of time he/she spent in the restroom; 1. how often have thesubject's bladder symptoms made him/her avoid activities away fromrestrooms (e.g., walking, running, hiking); m. how often have thesubject's bladder symptoms awakened the subject during sleep; n. howoften have the subject's bladder symptoms caused the subject to decreasehis or her physical activities (exercising, sports, etc.); o. how oftenhave the subject's bladder symptoms caused the subject to have problemswith his/her partner or spouse; p. how often have the subject's bladdersymptoms made the subject uncomfortable while traveling with othersbecause of needing to stop for a restroom; q. how often have thesubject's bladder symptoms affected his/her relationships with familyand friends; r. how often have the subject's bladder symptoms causedhim/her embarrassment; s. how often have the subject's bladder symptomscaused him/her to locate the closet restroom as soon as he/she arrive ata place he/she have never been.

Example 3 A Prospective, Multi-Center, Open-Label Study of TrospiumDelivered Intravesically by TAR-302-5018 to Subjects with IdiopathicOveractive Bladder (iOAB) and Urinary Incontinence—Part 1

TAR-302-5018 contains 850 mg of trospium chloride and has been shown torelease an average of 10 mg/day over a 42-day indwelling period in invitro studies. This average daily release rate is estimated to produce aurine concentration of 7 μg/mL in humans, assuming a urine productionrate of 1500 mL/day.

I. Objectives

Objectives of the study includes evaluating the safety and tolerabilityof one dosing cycle of TAR-302-5018 for up to 42 days, evaluating thepharmacokinetics (PK) of trospium exposure in urine and plasma duringthe 42-day indwelling period of TAR-302-5018, and determining theeffects of the intravesical continuous release of trospium on urinaryincontinence, urinary symptoms (frequency of micturition episodes andvoid volume), and quality of life (QoL) symptoms.

II. Methodology

Subjects with iOAB with urge urinary incontinence refractory to orintolerant to oral anticholinergic therapy were screened for inclusioninto the study. On Day 0, eligible subjects received TAR-302-5018transurethrally by way of the TARIS Inserter. On Day 42, TAR-302-5018was removed by way of either flexible or rigid cystoscopy. Subjects werefollowed during treatment for approximately 42 days after the removal ofTAR-302-5018 for safety and efficacy assessments which were completed onDay 84 (±7 days). In addition, PK assessments were performed at the Day0, Day 3 (±1 day), Day 7 (±1 day), Day 21 (±1 day), Day 35 (±2 days),Day 42, and Day 56 (±2 days) visits. Subjects were contacted by phone inbetween visits on Day 13 (±1 day), Day 27 (±1 day), Day 38 (±1 day), andDay 49 (±1 day) for safety assessments and reminders of studyprocedures.

Approximately 10 subjects were planned for inclusion in this part of thestudy. Twelve subjects were enrolled and underwent insertion ofTAR-302-5018; these 12 subjects were included in the Intent-to-Treat(ITT) Population and Safety Population. Eleven subjects completed thestudy and were included in the Per-Protocol (PP) Population.

III. Diagnosis and Main Criteria for Inclusion

To be eligible to participate in this study, the subject must have metall of the following inclusion criteria at the time of enrollment: 1.Symptoms of overactive bladder (OAB) (frequency/urgency) with urgeurinary incontinence or mixed urinary incontinence with a predominanturge component for at least 6 months. This means that the subject has 8or more voids per 24 hours as recorded in a diary and/or at least 4incontinence episodes associated with urgency recorded in a 3-day diary(or at least 1 episode must have occurred per each 24-hour day). 2.Inadequate response or limiting side effects with anticholinergics forthe treatment of OAB.

A subject was not eligible for inclusion in the study if any of thefollowing exclusion criteria applied: 1. Age <18 years. 2. OAB caused byneurological condition. 3. Presence of significant renal dysfunction atscreening (glomerular filtration rate <30 mL/min). 4. Presence ofsignificant polyuria of any cause at screening (urine output >4,000mL/day). 5. History of pelvic radiation. 6. History of either bladdercancer or bladder pathology that the investigator deemed unfit for studyinclusion. 7. Active malignancies within 12 months with the exception ofthose with a negligible risk of metastasis or death treated withexpected curative outcome. 8. Subjects with any bladder or urethralanatomic feature that may have prevented the safe placement, indwellinguse, or removal of TAR-302-5018. 9. In the opinion of the investigator,the subject had a history of significant stress urinary incontinence.10. Subjects with active bladder stones or history of bladder stones <6months prior to study entry. 11. History of recurrent symptomaticurinary tract infections (UTIs) (>4 per 1 year). 12. Subjects witheither urinary retention or gastric retention or uncontrollednarrow-angle glaucoma. 13. A post-void residual volume (PVR) of 300 mLor greater. 14. Subjects with known hypersensitivity to trospium,chemically-related drugs, or component excipients. 15. Subjects withknown hypersensitivity to the device materials, including silicone andnitinol. 16. Subjects actively taking oral trospium. 17. The addition ofa new or a change in dose to a current medication for the treatment ofOAB (i.e. anticholinergics, beta-3 adrenergic agonists, antispasmodics,antidepressants or hormones) within 30 days prior to signing theInformed Consent Form (ICF). A stable dose must have been continuedthrough the final study visit. If previously used and discontinued,these medications must have been stopped for >2 weeks prior to Day 0.18. Intravesical onabotulinum toxin use within the last 9 months priorto the Screening Visit. 19. Intravesical anticholinergic medicationswithin the last 30 days prior to the Screening Visit. 20. History ofnon-medication based therapy (i.e., Interstim therapy) for the treatmentof OAB. Non-invasive neuromodulation such as Percutaneous Tibial NerveStimulation (PTNS) was allowed if discontinued at least 8 weeks prior toDay 0. 21. Female subject who was pregnant (as verified by urine test attime of screening) or lactating or of childbearing potential and notusing acceptable methods of contraception. 22. Subject had a medicalcondition that may have caused noncompliance with the study protocol.23. Subject refused to provide written informed consent. 24. Subject wasunable or unwilling to complete the questionnaires and/or diaries andattend all protocol mandated study visits. 25. Participation in anotherdrug, device, or behavioral study within 60 days prior to the ScreeningVisit. 26. History or presence of any significant cardiovascular,pulmonary, hepatic, renal, gastrointestinal, gynecological, endocrine,immunological, dermatological, neurological or psychiatric disease ordisorder that, in the opinion of the investigator, contraindicatedparticipation. 27. History of any of the following within 3 months priorto Screening Visit: major illness/major surgery (requiringhospitalization), including pelvic, lower back surgery or procedureunrelated to bladder cancer; most outpatient procedures were notexclusionary; renal or ureteral stone disease or instrumentation;childbirth. 28. Difficulty providing blood samples. 29. Otherunspecified reasons that, in the opinion of the investigator or TARIS,made the subject unsuitable for enrollment.

IV. Endpoints

a. Primary Safety Endpoint.

Safety of TAR-302-5018 upon insertion, 42-day continuous exposure, andremoval. Safety was assessed via treatment-emergent adverse events(TEAEs), clinical laboratory tests, vital signs, physical examinations,bladder ultrasound, Investigational Product Event (IPEs), bladder PVRassessments, cystoscopic examination, and concomitant medications.

b. Secondary Safety Endpoints

Tolerability of TAR-302-5018 upon insertion, 42-day continuous exposure,and removal. Tolerability was defined as: not requiring removal prior tothe scheduled date due to meeting any of the protocol-specific SubjectStopping Criteria or other drug or device constituent related adverseevent (AE). PK analysis of plasma and urine (based on samples from Day0, Day 3 (±1 day), Day 7 (±1 day), Day 21 (±1 day), Day 35 (±2 day), Day42, and Day 56 (±2 days). Plasma and urine samples were used todetermine the following: Maximum concentration across visits (Cmax);Study Day of maximum concentration (Tmax); Concentration at removal onDay 42 (Ctau); Average concentration from Day 0 to 42 (Cave42); Averageconcentration from Day 0 to Day 56 (Cave56).

c. Preliminary Efficacy Endpoints.

Reduction in incontinence defined as a negative change from baseline innumber of daily episodes of urinary incontinence, where an event ofincontinence was defined as an incident of involuntary loss of urine, asrecorded in a subject bladder diary during the 3 days prior to the Day 0(baseline), Day 42, and Day 84 (±7 days) visits. Reduction in dailymicturition episodes defined as a negative change from baseline in thenumber of times a subject urinates into the toilet, as recorded in asubject diary during one 24-hour period prior to the Day 0 (baseline),Day 3 (±1 day), Day 7 (±1 day), Day 21 (±1 day), Day 35 (±2 days), Day42, and Day 56 (±2 days) visits. Exploratory assessment: increase invoided volume per micturition over baseline, measured over one 24-hourperiod prior to the Day 0 (baseline), Day 3 (±1 day), Day 7 (±1 day),Day 21 (±1 day), Day 35 (±2 days), Day 42, and Day 56 (±2 days) visitsand recorded by the subject in the diary.

d. Additional Efficacy Endpoint

Evidence of improvement in QoL as assessed by the OAB-q Short Form whichwas completed at the study site on Day 0, Day 42, and Day 84 (±7 days).

V. Statistical Methods

a. Analysis Populations.

ITT Population: Included all subjects enrolled and for whom theTAR-302-5018 insertion procedure on Day 0 was attempted, whethersuccessfully performed or not.

PP Population: Included all subjects in whom the TAR 302-5018 insertionprocedure was successfully performed and who retained TAR-302-5018 forthe complete 42-day treatment period without major protocol deviations.Major protocol deviations were defined prior to database lock.

Safety Population: Included all subjects enrolled and for whom theTAR-302-5018 insertion procedure was successfully performed. For thisstudy, the ITT and Safety Population were identical and results arepresented for the ITT Population.

b. Sample Size Determination.

The sample size was not based on statistical considerations.

c. Efficacy.

The number of incontinence episodes for 3 days prior to the specifiedvisits, the number of micturitions for 3 days prior to the specifiedvisits, and the total urine volume voided over each 24-hour collectionperiod were summarized descriptively by time point along with changesfrom baseline. A summary of subject response (subjects with a >50%decrease in incontinence episodes from baseline, a >75% decrease inincontinence episodes from baseline, and a 100% decrease in incontinenceepisodes from baseline) was presented for Day 42 and Day 84. Scores ofthe OAB-q Short Form were transformed as defined in the clinical studyreport. The transformed symptom severity scores and transformedhealth-related QoL scores were summarized descriptively by time point.

d. Pharmacokinetic.

Plasma and urine trospium were summarized descriptively by time point.Cmax, Tmax, Ctau, Cave42, and Cave56 for plasma and urine weresummarized descriptively.

e. Safety.

AEs were coded using the Medical Dictionary for Regulatory Activities(MedDRA) version 20.0. TEAEs were summarized by MedDRA system organclass and preferred term. TEAEs were also summarized by severity,relationship (to drug constituent, device constituent, or TARISInserter), and time period (Day 0 through 42, Day 42 through the Day 49[±1 day], and Day 0 through Day 49 [±1 day]). Serious adverse events(SAEs) were also summarized descriptively. Vital signs and laboratoryassessments along with the changes from baseline were summarizeddescriptively. Physical examination dates were listed. The number ofsubjects who were tolerant was presented for the TAR-302-5018 indwellingperiod. IPEs were summarized descriptively. Bladder PVR results weresummarized descriptively. Bladder ultrasound encrustation results werelisted by subject. Cystoscopic assessments of bladder urothelium werelisted by subject. Prior and concomitant medications were coded usingthe World Health Organization Drug Dictionary Enhanced (B3 Dec. 2017version) and were summarized descriptively.

VI. Summary and Conclusions

a. Efficacy Results

The mean number of incontinence episodes decreased by approximately 75%in the 3-day period prior to Day 42 and approximately 52% in the 3-dayperiod prior to Day 84 (±7 days) in the PP Population when compared tobaseline.

On Day 42, approximately 82% of subjects had a >50% decrease inincontinence episodes from baseline, 64% of subjects had a >75% decreasefrom baseline, and 27% of subjects had a 100% decrease from baseline inthe PP Population. On Day 84 (±7 days), approximately 46% of thesesubjects reported a >50% decrease from baseline and 18% reported a >75%decrease from baseline.

The mean number of micturition episodes in a 24-hour period decreasedfrom baseline at all post-baseline time points, with decreases ofapproximately 8%, 12%, 12%, 14%, 8%, and 11% were observed at Day 3 (±1day), Day 7 (±1 day), Day 21 (±1 day), Day 35 (±2 days), Day 42, and Day56 (±2 days), respectively, in the PP Population.

Mean 24-hour urine volumes decreased from baseline at Day 3 (±1 day),Day 7 (±1 day), Day 21 (±1 day), Day 35 (±2 days), Day 42, and Day 56(±2 days) in the PP Population. However, these findings were observedalong with decreases in bladder PVR.

Mean transformed symptom severity scores were decreased by approximately55% at Day 42 and approximately 26% at Day 84 (±7 days) in the PPPopulation, indicating decreased subject-reported symptom severity.

Mean transformed Health-Related Quality of Life (HRQL) scores increasedby approximately 143% at Day 42 and approximately 58% at Day 84 (±7days) in the PP Population, indicating greater subject-reported QoL.

b. Pharmacokinetic Results

Following insertion of the TAR-302-5018 system, trospium urineconcentrations were quantifiable in 9 of 11 subjects on Day 3 and in all11 subjects in the PP Population on Day 7 (±1 day) (with a mean Day 7concentration of 5258 ng/mL).

The majority of urine concentrations fell within the forecasted range of2000 to 6000 ng/mL, and target concentrations were maintained throughDay 42. Mean urine trospium concentrations were greatest on Day 21 (±1day) (mean of 5265 ng/mL), declined to 3822 ng/mL at Day 35 (±2 days)and 3565 ng/mL at Day 42.

Detectable plasma concentrations were infrequent. Samples withmeasurable trospium plasma concentrations did not exhibit a consistenttime course nor did the observed concentrations correlate with measuredurine concentration, urine volume or amounts recovered. Followingconfirmatory analyses using an independent bioanalytical method,external contamination of plasma samples is suspected to have affectedthe findings of 2 of the samples with detectable trospiumconcentrations. Excluding these 2 samples, trospium concentrationsacross the study were consistently low (<0.7 ng/mL).

Overall, the urine and plasma concentrations for this study weregenerally consistent with findings in previous nonclinical studies.

c. Safety Results

TAR-302-5018 was well tolerated. No subjects were considered to beintolerant to TAR-302-5018, based on the protocol-specified definitionof tolerability.

No subjects withdrew from treatment early due to either a TEAE or anIPE. One subject withdrew consent and discontinued TAR-302-5018 on Day21, and the remaining 11 subjects continued use of TAR-302-5018 asplanned through the Day 42 visit and completed the study.

The most common TEAEs during the treatment period of 42 days werehematuria (4/12 subjects; 33.3%), UTI (2/12 subjects; 16.7%), bladderpain (2/12 subjects; 16.7%), bladder discomfort (2/12 subjects; 16.7%),and sinusitis (2/12 subjects; 16.7%). The majority of AEs were mild.

One drug-related TEAE was reported: dry mouth. The most frequentdevice-related TEAEs were hematuria (4/12 subjects; 33.3%), bladderdiscomfort (2/12 subjects; 16.7%), and bladder pain (2/12 subjects;16.7%). Two subjects reported at least one TARIS Inserter-related TEAE.The events included: nausea, vomiting, chills, pyrexia, UTI, increasedwhite blood cell count, lactic acidosis, dysuria, hematuria, andperinephric edema, all in one subject (8.3%), and 1 report of urethralpain in the other subject (8.3%).

Mean changes from baseline in laboratory parameters were generallysmall. Post-baseline findings of occult blood (at any level) weregreatest at Day 21 (±1 day) (41.7%) and decreased to 27.3% at Day 42 and9.1% at Day 84 (±7 days). Four subjects had hematuria findings that werereported as TEAEs; one of these reports was in the subject with the SAEof UTI.

Mean changes from baseline in blood pressure, heart rate, respiratoryrate, and body temperature were small and not clinically meaningful. Nosubjects had a TEAE related to a vital sign abnormality.

Mean bladder PVR decreased from screening by approximately 21%, 42%, and29% at Days 7 (±1 day), 21 (±1 day), and Day 35 (±2 days), respectively.

There were no observations of urothelial bleeding, no evidence ofbladder stones, and no evidence of bladder diverticula were observedupon cystoscopy. No cases of encrustation were observed upon bladderultrasound assessments on Day 21 (±1 day) or upon removal.

One IPE was reported, which included damage to the TAR-302-5018 whichthe investigator suspected occurred while grasping the system forremoval. The subject did not report discomfort or any other TEAEs.

d. Conclusion.

Overall, TAR-302-5018 was found to have an acceptable safety profile,was well tolerated over the 42-day indwelling period, and consistentlyproduced urine concentrations in the targeted and expected range, withlimited systemic exposure. Notable decreases in the number of urgeurinary incontinence episodes were observed in this patient population,along with decreases in the number of micturitions, decreases insubject-reported symptom severity scores, and improvements in QoL. Thegreatest effects were observed at Day 42, however, persistent andmeaningful improvements from baseline were still evident at the finalstudy assessment occurring 6 weeks after removal of TAR-302-5018.

Example 4 A Prospective, Multi-Center, Open-Label Study of TrospiumDelivered Intravesically by TAR-302-5018 to Subjects with IdiopathicOveractive Bladder (iOAB) and Urinary Incontinence—Part 2

Trospium-Releasing Intravesical System (TAR-302-5018) is placed into thebladder through an inserter on Study Day 0 and is removed on Study Day84. TAR-302-5018 releases trospium gradually during the 84 dayindwelling time.

I. Outcome Measures

Safety of TAR-302-5018 was assessed on days 0, 14, 56, 84, and 112, asshown in FIG. 15A. Safety was assessed throughout the study based onreported AEs, investigational product events (IPEs), physicalexaminations (PEs), vital signs, clinical laboratory tests, scheduledcystoscopic examinations, bladder ultrasounds, bladder post-voidresidual volume (PVR), and the use of concomitant medications.

Tolerability of TAR-302-5018 was assessed. Percent of subjects who aretolerant of TAR-302-5018 indwelling for the designated period of timeand do not require TAR-302-5018 removal prior to the scheduled date ofremoval due to meeting any of the Subject Stopping Criteria or otherdrug or device constituent related adverse event.

Pharmacokinetic Analysis of Plasma and Urine [Time Frame: From Day 0 toDay 112] was conducted. It includes analysis of plasma trospium exposureand urinary trospium exposure.

Reduction in incontinence over baseline [Time Frame: From Day 0 to Day112] was assessed. A change from baseline in number of daily episodes ofurinary incontinence was assessed, where incontinence is defined as anincident of involuntary loss of urine.

Reduction in daily micturition episodes [Time Frame: From Day 0 to Day112] was assessed. A change from baseline in the number of times asubject urinates into the toilet was be assessed.

Increase in voided volume per micturition [Time Frame: From Day 0 to Day112] was assessed. A change from baseline as measured over separate24-hour periods was be assessed.

Other outcome measures include quality of life score and bother score asassessed by the OAB-q short form.

II. Inclusion Criteria

Patients with symptoms of idiopathic overactive bladder (iOAB)(frequency/urgency) with urge urinary incontinence or mixed urinaryincontinence with a predominant urge component for at least 6 monthswere be included. These patients may have 8 or more voids per 24 hoursas recorded in a diary or at least 4 incontinence episodes associatedwith urgency recorded in a 3-day diary (or at least 1 episode occurs pereach 24 hour day).

Patients were also be included if, in the opinion of the investigator,the subject has experienced an inadequate response to or limiting sideeffects with prior oral medications for the treatment of OAB.

III. Exclusion Criteria

Patients that fulfill any of the conditions listed below wereexcluded. 1. Age <18 years. 2. Neurologic bladder condition. 3. Subjectswith Diabetes Mellitus (both Type 1 & Type 2) must demonstrate optimalglycemic control with HbA1c levels <7.5% and an absence of significantglycosuria defined as 3+ glucose via dipstick at screening. 4. Presenceof significant polyuria of any cause at screening (urine output >3,000mL/day). 5. Presence of nocturnal polyuria at time of study screeningdefined as >30% of total 24-hour urine collected from time of evening(P. M.) sleep and inclusive of the first morning (A. M.) void. 6.History of pelvic irradiation. 7. History of either bladder cancer orbladder pathology that the investigator deems unfit for study inclusion.8. Currently uses intermittent catheterization (IC) to empty the bladderwithin 30 days of Day 0. 9. Subjects with any bladder or urethralanatomic feature (e.g., urethral stricture) that in the opinion of theinvestigator may prevent the safe placement, indwelling use, or removalof IP. 10. Subjects with active bladder stones or history of bladderstones <6 months prior to study entry. 11. Gross hematuria within 30days of Day 0. 12. History of uncontrolled bleeding, bleeding diathesis,or underlying coagulopathy within 30 days of Day 0. 13. In the opinionof the investigator, the subject has a history of predominance ofsignificant stress urinary incontinence. 14. History of >2 symptomaticurinary tract infections in the 6-months prior to Day 0. 15. Subjectswith either urinary retention or gastric retention or uncontrollednarrow-angle glaucoma within 90 days of Day 0. 16. A post-void residualvolume (PVR) of 100-mL or greater. 17. Subjects with knownhypersensitivity to trospium, chemically-related drugs, or componentexcipients. 18. Subjects with known hypersensitivity to the devicematerials, including silicone and nitinol. 19. Anticholinergic or beta-3agonist use for the treatment of urge urinary incontinence <2 weeksprior to Day 0. 20. History of intravesical onabotulinum toxin usewithin the last 9 months prior to the Screening Visit. 21. Intravesicalanticholinergic medications within the last 14 days prior to theScreening Visit. 22. History of procedural-based neuromodulation therapy(e.g. InterStim therapy, Percutaneous Tibial Nerve Stimulation [PTNS])for the treatment of OAB. 23. Female subject who is pregnant (asverified by serum test at time of screening) or lactating. 24. Subjecthas, in the opinion of the investigator, a medical condition that maycause noncompliance with the study protocol. 25. Subject who is unableor unwilling to complete the questionnaires, diaries, or attend allprotocol mandated study visits. 26. Participation in another drug,device, or behavioral study within 60 days prior to the Screening Visit.27. History or presence of any significant cardiovascular, pulmonary,hepatic, renal, gastrointestinal, gynecological, endocrine,immunological, dermatological, neurological or psychiatric disease ordisorder, or other unspecified reasons that, in the opinion of theinvestigator or TARIS, make the subject unsuitable for enrollment. 28.History of any of the following within 3 months prior to ScreeningVisit: i. Major illness/major surgery (requiring hospitalization),including pelvic, lower back surgery or procedure; most outpatientprocedures are not exclusionary; ii. Childbirth. 29. History ofprostatic biopsy or surgery (ablative or non-ablative) within 6 monthsprior to Day 0. 30. History of significant pelvic organ prolapse(Grade>/=3). 31. Difficulty providing blood samples. 32. Known historyof drug or alcohol dependency within 12 months of screening. 33. Otherunspecified reasons that, in the opinion of the investigator or TARIS,make the subject unsuitable for enrollment

Daily incontinence events were assessed on days 0, 14, 56, 84, and 112,as shown in FIG. 15A. As shown in FIG. 15B, prior to treatment, patientsexperienced an average of 5.23 incontinence episodes per day. At day 14,the average daily incontinence episodes were reduced to 2.9, a 44%decrease from baseline. At day 56, the average daily incontinenceepisodes were reduced to 3.0, a 43% decrease from baseline. At day 84,the average daily incontinence episodes were reduced to 2.3, a 56%decrease from baseline. This indicates that extended local delivery oftrospium to the bladder is effective for treating overactive bladder.

The invention claimed is:
 1. A method of training the bladder of anindividual having idiopathic overactive bladder comprising administeringan effective amount of trospium locally to the bladder of the individualfor at least about 24 hours, wherein the individual experiences at leastabout 40% of baseline symptom relief for at least about 7 days aftertrospium administration is completed.
 2. A method of prolonging symptomrelief for an individual having idiopathic overactive bladder comprisingadministering an effective amount of trospium locally to the bladder forat least about 24 hours, wherein the individual experiences at leastabout 40% of baseline symptom relief for at least about 7 days aftertrospium administration is completed.
 3. A method of improving thequality of life of an individual having idiopathic overactive bladdercomprising administering an effective amount of trospium locally to thebladder for at least about 24 hours, wherein the individual has animproved quality of life score and/or a reduced urinary bother scoreupon treatment with trospium, wherein the individual experiences atleast about 40% of baseline symptom relief for at least about 7 daysafter trospium administration is completed.
 4. The method of claim 2,wherein the individual having overactive bladder experiences at leastabout 50% of baseline symptom relief for at least about 7 days aftertrospium administration is completed.
 5. The method of claim 2 whereintrospium is continuously administered locally to the bladder for atleast about 42 days.
 6. The method of claim 2 wherein the method furthercomprises administering an effective amount of trospium locally to thebladder every 3 months or on an as needed (prn) basis.
 7. A method oftreating idiopathic overactive bladder comprising continuouslyadministering an effective amount of trospium locally to the bladder ofthe individual for at least about 42 days.
 8. The method of claim 7,wherein trospium is continuously administered for about 84 days.
 9. Themethod of claim 7, wherein trospium is continuously administered for atleast about 12 weeks.
 10. A method of maintenance therapy for idiopathicoveractive bladder in an individual comprising administering trospiumcontinuously and locally to the bladder for at least about 24 hours,wherein the individual has received a previous therapy for overactivebladder, wherein the individual experiences at least about 40% ofbaseline symptom relief for at least about 7 days after trospiumadministration is completed.
 11. The method of claim 10, wherein themaintenance therapy comprises administering an effective amount oftrospium locally to the bladder for at least about 24 hours every 3months.
 12. The method of claim 10, wherein the maintenance therapycomprises administering an effective amount of trospium locally to thebladder for at least about 24 hours on an as needed (prn) basis.
 13. Themethod of claim 10, wherein the maintenance therapy comprisesadministering an effective amount of trospium locally to the bladder forat least about 24 hours upon symptom recurrence.
 14. The method of claim10, wherein the maintenance therapy comprises administering an effectiveamount of trospium locally to the bladder for at least about 24 hourswhen the individual experiences at least a 50% recurrence in baselinesymptoms.
 15. The method of claim 10, wherein the previous therapycomprises administering an effective amount of trospium locally to thebladder for at least about 42 days.
 16. The method of claim 2, whereinthe concentration of trospium in the bladder is between 0.1 to 100 μg/mlduring administration of trospium.
 17. The method of claim 2, whereinthe concentration of trospium in the plasma of the individual is lessthan 2 ng/ml during administration of trospium.
 18. The method of claim2, wherein the individual has failed a previous treatment for overactivebladder.
 19. The method of claim 2, wherein the individual has notreceived a previous treatment for overactive bladder.
 20. The method ofclaim 2, wherein the individual has failed or is not eligible for oraltherapy.
 21. The method of claim 2, wherein the individual has urinaryincontinence or urge incontinence.
 22. The method of claim 2, whereinthe method results in neuronal remodeling or remodeling of a neuralnetwork.
 23. The method of claim 2, wherein symptomatic relief ofurgency, frequency, or incontinence is achieved.
 24. The method of claim2, wherein the quality of life score of the individual is improved. 25.The method of claim 2, wherein the urinary bother score of theindividual is reduced.
 26. The method of claim 2, wherein the methodreduces an aberrant urge to urinate.
 27. The method of claim 2, whereintrospium is administered to the bladder by using an intravesical device.28. The method of claim 2, wherein an effective amount of trospium isadministered locally to the bladder for at least about 42 days.
 29. Themethod of claim 2, wherein an effective amount of trospium isadministered locally to the bladder for at least about 84 days.
 30. Themethod of claim 2, wherein the individual has failed a previoustreatment for overactive bladder.
 31. The method of claim 2, wherein theindividual has not received a previous treatment for overactive bladder.32. The method of claim 2, wherein the individual has failed or is noteligible for oral therapy.
 33. The method of claim 2, wherein theindividual has urinary incontinence or urge incontinence.
 34. The methodof claim 7, wherein the method results in neuronal remodeling orremodeling of a neural network.
 35. The method of claim 7, whereinsymptomatic relief of urgency, frequency, or incontinence is achieved.36. The method of claim 7, wherein trospium is administered to thebladder by using an intravesical device.
 37. The method of claim 10,wherein an effective amount of trospium is administered locally to thebladder for at least about 42 days.
 38. The method of claim 10, whereinan effective amount of trospium is administered locally to the bladderfor at least about 84 days.
 39. The method of claim 10, wherein theindividual has failed a previous treatment for overactive bladder. 40.The method of claim 10, wherein the individual has not received aprevious treatment for overactive bladder.
 41. The method of claim 10,wherein the individual has failed or is not eligible for oral therapy.42. The method of claim 10, wherein the individual has urinaryincontinence or urge incontinence.
 43. The method of claim 10, whereinthe method results in neuronal remodeling or remodeling of a neuralnetwork.
 44. The method of claim 10, wherein symptomatic relief ofurgency, frequency, or incontinence is achieved.
 45. The method of claim10, wherein trospium is administered to the bladder by using anintravesical device.